Oligopeptides And Their Use In Cosmetics

ABSTRACT

The present invention relates to the cosmetic use of oligopeptides, cosmetic preparations which comprise such oligopeptides as well as certain oligopeptide derivatives themselves.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 11/665,810 filed Apr. 18, 2007, which claims priority to International Application No. PCT/EP2005/010893 filed Oct. 10, 2005, and published in English on Apr. 27, 2006, as WO 2006/042661 A3, which claims priority from European Application No. 04292475.3 filed Oct. 18, 2004, each of which is incorporated herein by reference in its entirety.

REFERENCE TO SEQUENCE LISTING

The Sequence Listing submitted on Oct. 29, 2008, in parent application U.S. application Ser. No. 11/665,810, (85 pages containing 375 oligopeptide sequences) is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the cosmetic use of oligopeptides, cosmetic preparations which comprise such oligopeptides as well as certain oligopeptide derivatives themselves.

BACKGROUND OF THE INVENTION

Cosmetic preparations are available nowadays to the consumer in a large number of combinations. In this regard, it is not only expected that these cosmetics exhibit a particular care effect or overcome a certain deficiency, but there is an evermore frequent requirement for products which have several properties at the same time and thus exhibit an improved performance spectrum. Of particular interest are substances which both favourably influence the technical properties of the cosmetic product, such as storage stability, photostability and ability to be formulated, and also at the same time constitute active ingredients which confer care, irritation suppressing and/or photoprotective properties for skin and/or hair for example. Additionally, good skin compatibility and particularly the use of natural products are requested by the customer. There is a further need for effective protection of the skin against environmental ageing effects.

The human skin expresses a number of antimicrobially effective peptides, such as, for example, cathelicidin and 13-defensin, during inflammation processes of the skin such as wound healing, contact dermatitis and psoriasis. It is known that these peptides in the skin construct a barrier for protecting the endogenous skin cells against microbial pathogenesis (Gallo R L & Huttner K M. J. Invest. Dermatol. 1998, 111, 739-43). The peptide cathelicidin PR39 was identified for the first time in wound fluid of pigs through the induction of syndecan (Gallo R-L., Proc Natl. Acad. Sci. USA, 1994, 91, 11035-11039). Supplementary to this prior art, it is reported that in the case of fragment 1-15 of PR39 the antimicrobial properties of the peptide remain completely intact. It was shown that the interaction of the fragment with the lipid double layer is identical to the complete peptide and that the fragment binds with SH3-containing proteins (Chan Y. R, Gallo R L., J. Biol. Chem. 1998, 273, 2897-28985). The same team was then able to show that the N-terminal region is important for peptide activity and specifically for the syndecan induction and the antimicrobial activity and that the C-terminal region is of greater importance for the antibacterial properties (Chan Y. R., Gallo R. L., J. Invest. Dermat. 2001, 116, 230-235).

WO 01/47540 describes a method for selectively inhibiting degradation of IkBa using oligopeptides of PR-39. The following oligopeptides of PR-39 are disclosed: the oligopeptide consisting of the 15 aminoterminal amino acids, the oligopeptide consisting of the 11 aminoterminal amino acids, and the oligopeptide consisting of the 8 aminoterminal amino acids. WO 01/30368 describes a method for stimulating angiogenesis with oligopeptides of PR-39 using the oligopeptides as described in WO 01/47540. Gallo R L et al. PNAS 91, 11035-39 (1994) describes the antibacterial activity of the peptide PR39 and its ability to induce syndecan. Gaczynska M. et al Biochemistry, 2003, 42, 8663-8670 describes that the shortest functional derivative from PR 39 to still show allosteric inhibitory effects consist of eleven amino-terminal residues. Zaiou M & Gallo R L J Mol Med 80, 549-61 (2002) review the different know activities of PR-39, e.g. induction of syndecan expression, chemoattractant activity etc. Gudmundsson G. et al PCNAS 92, 7085-89 (1995) describes the gene for PR-39.

U.S. Pat. No. 6,713,605 (WO 96/32129) describes PR-39 and truncated analogs consisting of 26, 23, 19, 16, 15, 14, 7 and 6 amino acids of PR-39 and their use as medicaments for inhibiting leucocyte superoxide anion production. WO 00/43417 describes peptides H-Arg-Pro-(AA)n-OH or H-Pro-Arg-(AA)n-OH, wherein n=0 to 3. WO 00/43317 describes the use of these penta-petides for the regulation of immunological dysfunction and in cutaneous inflammation. Specifically disclosed are the following peptides: Arg Pro Arg (SEQ ID NO. 366), Arg Lys Pro Arg (SEQ ID NO. 367), Thr Lys Pro Arg (SEQ ID NO. 368), N-Palmitoyl-Thr Lys Pro Arg (SEQ ID NO. 369), Gly Gln Pro Arg (SEQ ID NO. 370), N-Palmitoyl-Gly Gln Pro Arg (SEQ ID NO 371), Phe-Tyr-Arg-Pro-Arg (SEQ ID NO. 372), Ala-Arg-Asp-Pro-Arg (SEQ ID NO. 373).

Cosmetic preparations comprising peptides with a large number of amino acids, such as, for example, the entire cathelicidin PR-39, are not practicable and sometimes also not realizable because the production of this type of peptides on an industrial scale is very difficult and very expensive.

The object of the present patent application was to provide cosmetic preparations which lead to protection of the skin, scalp, mucosa and/or hair against environmental effects, oxidative stress, toxic substances or UV radiation and to a stimulation of the renewal rate of skin and/or hair and can thus be used effectively in cosmetics for topical application. It was also an object of the present invention to provide oligopeptides as well as cosmetic preparations having the above mentioned specified profile of requirements and at the same time the shortest possible number of amino acids.

Surprisingly, it has now been found that oligopeptides comprising amino acids of the peptide cathelicidin PR-39 satisfy the requirements made. None of the document of the prior art describes oligopeptides of the invention nor the cosmetic use of the claimed oligopeptides. None of the documents describes oligopeptides which can be used for stimulating the renewal rate of skin and/or hair or cosmetic compositions comprising oligopeptides with such a profile.

DESCRIPTION OF THE INVENTION Cosmetic Use of Oligopeptide of Formula (I)

The current invention relates to the cosmetic use of oligopeptides with the structure of formula (I)

R1-[AA]_(n)-R2  (I)

wherein [AA] comprises at least 4 consecutive amino acids, which are identical compared to 4 consecutive amino acids of SEQ ID NO.1 and/or wherein [AA] comprises at least 6 amino acids, of which 4, preferably 5 are identical compared to 6 consecutive amino acids of SEQ ID NO. 1 wherein n=4 to 15, preferably n=4 to 10 wherein R1 is linked to the NH₂ group of the amino-terminal part of [AA] and is chosen from the group which is formed from

-   -   a) —H,     -   b) a linear saturated or unsaturated or branched saturated or         unsaturated acyl group having 1 to 24 carbon atoms, which may be         functionalized by a —OH, —SH, —COOH or —CONH₂ group,     -   c) a sterol or a spingolipid group which is joined to the amino         terminal part of [AA] via a bifunctional linker         wherein R2 is linked to the 0=0 group of the carboxy-terminal         part of [AA] and is chosen from the group which is formed from     -   a) —OH,     -   b) —NH₂     -   c) a linear saturated or unsaturated or branched saturated or         unsaturated alkoxy group having 1 to 24 carbon atoms     -   d) or a sterol or a sphingolipid group.

The term “oligopeptide” encompasses single species of formula (I) as well as mixtures of at least 2, at least 3 or more oligopeptides of formula (I).

Oligopeptide (I)

A further embodiment of the invention is directed to oligopeptides with the structure of formula (I)

R1-[AA]_(n)-R2  (I)

wherein [AA] comprises at least 4 consecutive amino acids, which are identical compared to 4 consecutive amino acids of SEQ ID NO.1 and/or wherein [AA] comprises at least 6 amino acids, of which 4, preferably 5, more preferably 6 are identical compared to 6 consecutive amino acids of SEQ ID NO.1 wherein n=4 to 15 wherein R1 is linked to the NH₂ group of the amino-terminal part of [AA] and is chosen from the group consisting of

-   -   a) —H,     -   b) is a linear saturated or unsaturated or branched saturated or         unsaturated acyl group having 1 to 24 carbon atoms, which may be         functionalised by a —OH, —SH, —COOH or —CONH₂ group,     -   c) a sterol or a spingolipid group which is joined to the amino         terminal part of [AA] via a bifunctional linker         wherein R2 is linked to the C═O group of the carboxy-terminal         part of [AA] and is chosen from the group which is formed from     -   a) —OH,     -   b) —NH₂     -   c) is a linear saturated or unsaturated or branched saturated or         unsaturated alkoxy group having 1 to 24 carbon atoms, which may         be functionalised by a —OH, —SH, —COOH or —CONH₂ group, or     -   d) a sterol or a sphingolipid group,         with the proviso that if R1 is —H, R2 is not —OH; or that if R2         is —OH, R1 is not —H, and with the proviso that if R1 is —H, R2         is chosen form the group which is formed from     -   b) —NH₂     -   c) a linear saturated or unsaturated or branched saturated or         unsaturated alkoxy group having 2 to 24 carbon atoms, or     -   d) a sterol or a sphingolipid group.

These oligopeptides are especially useful in cosmetic preparations.

The total number of amino acids in the oligopeptide (=n) be any number between 4 and 15, thus n can be 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In a preferred embodiment the total number of amino acids is at most 15, preferably at most 12, preferably at most 10, preferably at most 8, preferably at most 6, preferably at most 5.

The terms “oligopeptide” and “oligopeptides” are used synonymously to encompass single oligopeptide species of formula (I) as well as mixtures of at least 2, at least 3, or more oligopeptides according to formula (I). In case where at least R1 is not ═H or R2 is not —OH, the term “oligopeptide derivative” would be a more precise term. As used in this description, the term “oligopeptide” or “oligopeptides” encompasses oligopeptides as well as oligopeptide derivatives as well as salt of the oligopeptides as well as salts of the oligopeptide derivatives.

In a further embodiment of the invention, oligopeptides which are able to stimulate the growth of human keratinocytes in-vitro are preferred.

This ability can be tested in standard assays using human primary keratinocytes, which can be obtained by trypsinization of human skin biopsis. These are cultured in standard medium under standard conditions prior to the cultivation of the oligopeptide to be tested. Usual cultivation with the oligopeptide to be tested is 37° C., 4 or 5 days.

The stimulation of the proliferation can be determined by measuring the number of living cells in a sample cultivated with the oligopeptide to be tested in comparison to control (=no peptide). The number of living cells can for example be determined by measuring the DNA content, e.g. by fluorescence methods.

A stimulation of the proliferation is preferably achieved, if 5% more DNA is detected, preferably 10% more, even more preferably 15% more, even more preferably 20% more DNA when compared to the DNA content of the control.

Cosmetic Use

It has been found that the oligopeptides according to the invention are especially useful for producing a preparation which is effective against the formation of wrinkles and/or for reducing the severity of wrinkles and/or against the loss of elasticity of the skin and/or for strengthening the cutaneous barrier and/or dermis and/or the dermalepidermal junction (DEJ) and/or for reducing the skin dryness and/or for reducing the “orange skin” phenomenon of subcutaneous tissue. The oligopeptides according to formula (I) are preferably used for stimulating the renewal rate of skin and/or hair. They are preferably useful in cosmetic preparations against the reduction in cell numbers in human skin or for stimulating and/or regenerating hair growth and against hair loss.

It has surprisingly been found that the oligopeptides according to the invention are useful in strengthening of the cutaneous barrier and reducing the skin dryness at the same time.

In one embodiment, the oligopeptide according to the invention are useful for the cosmetic treatment of

-   -   a. human skin or hair ageing and/or     -   b. for preventing against ageing symptoms, such as wrinkles,         and/or     -   c. decrease of the epidermal and dermal skin layers, and/or     -   d. alterations of the extracellular matrix and/or decrease in         the renewal of epidermal and dermal cells and/or     -   e. modifications of the dermal epidermal junctions and/or     -   f. loss of elasticity and/or     -   g. hair damages and/or hair losses.

In one embodiment, the oligopeptide according to the invention are preferably useful for

-   -   h. stimulation of the renewal rate of human skin and/or hair.

In a preferred embodiment, the oligopeptide according to the invention are used for cosmetic preparations which are effective

-   -   i. for stimulating the production of mRNA and/or     -   j. for stimulation of matrix proteins such as collagen, elastin         or proteoglycans and/or     -   k. for stimulation of syndecan-1 synthesis

It has surprisingly been found, that the oligopeptides according to this invention are especially useful in cosmetic compositions for stimulating syndecan-1 synthesis.

In a preferred embodiment, the oligopeptides according to the invention, are used for producing a preparation which is effective against the formation of wrinkles and for reducing the severity of wrinkles or against the loss of elasticity of the skin or for strengthening the cutaneous barrier and/or the dermis and/or the dermal-epidermal junction (DEJ) or for reducing the “orange skin” phenomenon of subcutaneous tissue or for improved wound healing or against the reduction in cell numbers in human skin.

In one embodiment of the invention the oligopeptides according to the invention are used for stimulating and/or regenerating hair growth and against hair loss. In a preferred embodiment of the invention the oligopeptides are used in cosmetic preparations which stimulate the growth and the differentiation of human primary keratinocytes, which strenghten the skin barrier function. Preferably the oligopeptides according to the invention can be used effectively as inhibitors of elastase, the enzyme which degrades elastin.

[AA] Moiety: Tetrapeptide

In one embodiment of the invention, [AA] consists of 4 consecutive amino acids, which are identical to 4 consecutive amino acids of SEQ ID NO.1.

Table 1 lists these tetra-peptides:

36 tetra peptides of 4 consecutive amino acids of SEQ ID NO. 1 Seq. ID NO. Column I Seq. ID NO. 2 Arg Arg Arg Pro Seq. ID NO. 3 Arg Arg Pro Arg Seq. ID NO. 4 Arg Pro Arg Pro Seq. ID NO. 5 Pro Arg Pro Pro Seq. ID No. 6  Arg Pro Pro Tyr Seq. ID NO. 7 Pro Pro Tyr Leu Seq. ID NO. 8 Pro Tyr Leu Pro Seq. ID NO. 9 Tyr Leu Pro Arg Seq. ID NO. 10 Leu Pro Arg Pro Seq. ID NO. 11 Pro Arg Pro Arg Seq. ID NO. 12 Arg Pro Arg Pro Seq. ID NO. 13 Pro Arg Pro Pro Column II Seq. ID NO. 14 Arg Pro Pro Pro Seq. ID NO. 15 Pro Pro Pro Phe Seq. ID NO. 16 Pro Pro Phe Phe Seq. ID NO. 17 Pro Phe Phe Pro Seq. ID NO. 18 Phe Phe Pro Pro Seq. ID NO. 19 Phe Pro Pro Arg Seq. ID NO. 20 Pro Pro Arg Leu Seq. ID NO. 21 Pro Arg Leu Pro Seq. ID NO. 22 Arg Leu Pro Pro Seq. ID NO. 23 Leu Pro Pro Arg Seq. ID NO. 24 Pro Pro Arg Ile Seq. ID NO. 25 Pro Arg Ile Pro Column III Seq. ID NO. 26 Arg Ile Pro Pro Seq. ID NO. 27 Ile Pro Pro Glu Seq. ID NO. 28 Pro Pro Glu Phe Seq. ID NO. 29 Pro Glu Phe Pro Seq. ID NO. 30 Glu Phe Pro Pro Seq. ID NO. 31 Phe Pro Pro Arg Seq. ID NO. 32 Pro Pro Arg Phe Seq. ID NO. 33 Pro Arg Phe Pro Seq. ID NO. 34 Arg Phe Pro Pro Seq. ID NO. 35 Phe Pro Pro Arg Seq. ID NO. 36 Pro Pro Arg Phe Seq. ID NO. 37 Pro Arg Phe Pro

In a preferred embodiment [AA] consists of a tetra-peptide as specified in column I of table 1.

In a preferred embodiment [AA] consists of a tetra-peptide selected from the group consisting of

-   -   i) Arg Arg Arg Pro (SEQ ID NO. 2); Arg Arg Pro Arg (SEQ ID NO.         3);     -   ii) Arg Pro Pro Tyr (SEQ ID NO. 6); Pro Pro Tyr Leu (SEQ ID NO.         7); preferably Pro Pro Tyr Leu (SEQ ID NO. 7);     -   iii) Pro Tyr Leu Pro (SEQ ID NO. 8); Tyr Leu Pro Arg (SEQ ID NO.         9); or     -   iv) Tyr Leu Pro Arg (SEQ ID NO. 9); Leu Pro Arg Pro (SEQ ID NO.         10).

In a further embodiment the oligopeptide consists of at most 15, preferably at most 10, more preferably at most 5 amino acids, of which at least 4 consecutive amino acids are identical to 4 consecutive amino acids of SEQ ID NO.1. Thus in one embodiment of the invention, [AA] comprises 4 consecutive amino acids which are identical to 4 consecutive amino acids of SEQ ID NO.1 and has up to 11 further amino acids (resulting in a total number of 15 amino acids), preferably up to 6 further amino acids (resulting in a total number of 10 amino acids), more preferably up to 1 further amino acid (resulting in a total number of 5 amino acids), whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)], wherein aa is a tetra-peptide of table 1 and X and Y are further amino acids, m and 0 being numbers from 0 to 11, with the proviso that m+o is ≦11. In a preferred embodiment, aa is selected from the tetrapeptides as specified in column 1 of table 1. In a further preferred embodiment m+o is ≦6, preferably =1.

In a preferred embodiment [AA] comprises a tetra-peptide as specified in column I of table 1.

In a preferred embodiment [AA] comprises a tetra-peptide selected from the group consisting of

-   -   i) Arg Arg Arg Pro (SEQ ID NO. 2); Arg Arg Pro Arg (SEQ ID NO.         3);     -   ii) Arg Pro Pro Tyr (SEQ ID NO. 6); Pro Pro Tyr Leu (SEQ ID NO.         7), preferably Pro Pro Tyr Leu (SEQ ID NO. 7)     -   iii) Pro Tyr Leu Pro (SEQ ID NO. 8); Tyr Leu Pro Arg (SEQ ID NO.         9); or     -   iv) Tyr Leu Pro Arg (SEQ ID NO. 9); Leu Pro Arg Pro (SEQ ID NO.         10).

The further amino acids can be any of the known proteinogenic amino acids including selenocystein (Sec) and L-pyrrolysine, derivatives of the proteinogenic amino acids or non-proteinogenic amino acids, e.g. L-citrullin. L-homocysteine, L-homoserine, (4R)-4-hydroxy-L-prolin, L-Homoserin (Hse), (4R)-4-Hydroxy-L-proline (Hyp), (5R)-5Hydroxy-L-lysine (Hyl), L-ornithine (am), sarkosine to name only a few. Functional groups of the further amino acids can be derivatised, e.g. by linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24 carbon atoms, by functional groups such as a —OH, —SH, —COOH or —CONH₂ group.

The amino acids can be either in D- or in L-configuration.

In a further embodiment of the invention [AA] comprises at most 14, preferably at most 13, preferably at most 13, preferably at most 12, more preferably at most 10, preferably at most 9, preferably at most 8, preferably at most 7, preferably at most 6, preferably at most 5 consecutive amino acids identical to the respective amino acids of the amino acid sequence of SEQ ID NO.1.

In a preferred embodiment of the invention [AA] consists of at most 15, preferably at most 14, preferably at most 13, preferably at most 13, preferably at most 12, more preferably at most 10, preferably at most 9, preferably at most 8, preferably at most 7, preferably at most 6, preferably at most 5 consecutive amino acids identical to the respective amino acids of the amino acid sequence of SEQ ID NO.1.

[AA] Moiety: Pentapeptide

In a further embodiments of the invention [AA] comprises at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14 or consists of 15 consecutive amino acids which are identical to the respective number of amino acids of SEQ ID NO.1.

In a further embodiments of the invention [AA] consists of at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14 consecutive amino acids which are identical to the respective number of amino acids of SEQ ID NO.1.

In one embodiment of the invention, [AA] consists of 5 consecutive amino acids, which are identical to 5 consecutive amino acids of SEQ ID NO.1.

TABLE 2 35 penta-peptides of 5 consecutive amino acids of SEQ ID NO. 1 Seq. ID NO. Column I Seq. ID NO. 38 Arg Arg Arg Pro Arg Seq. ID NO. 39 Arg Arg Pro Arg Pro Seq. ID NO. 40 Arg Pro Arg Pro Pro Seq. ID NO. 41 Pro Arg Pro Pro Tyr Seq. ID NO. 42 Arg Pro Pro Tyr Leu Seq. ID NO. 43 Pro Pro Tyr Leu Pro Seq. ID NO. 44 Pro Tyr Leu Pro Arg Seq. ID NO. 45 Tyr Leu Pro Arg Pro Seq. ID NO. 46 Leu Pro Arg Pro Arg Seq. ID NO. 47 Pro Arg Pro Arg Pro Seq. ID NO. 48 Arg Pro Arg Pro Pro Column II Seq. ID NO. 49 Pro Arg Pro Pro Pro Seq. ID NO. 50 Arg Pro Pro Pro Phe Seq. ID NO. 51 Pro Pro Pro Phe Phe Seq. ID NO. 52 Pro Pro Phe Phe Pro Seq. ID NO. 53 Pro Phe Phe Pro Pro Seq. ID NO. 54 Phe Phe Pro Pro Arg Seq. ID NO. 55 Phe Pro Pro Arg Leu Seq. ID NO. 56 Pro Pro Arg Leu Pro Seq. ID NO. 57 Pro Arg Leu Pro Pro Seq. ID NO. 58 Arg Leu Pro Pro Arg Seq. ID NO. 59 Leu Pro Pro Arg Ile Column III Seq. ID NO. 60 Pro Pro Arg Ile Pro Seq. ID NO. 61 Pro Arg Ile Pro Pro Seq. ID NO. 62 Arg Ile Pro Pro Glu Seq. ID NO. 63 Ile Pro Pro Glu Phe Seq. ID NO. 64 Pro Pro Glu Phe Pro Seq. ID NO. 65 Pro Glu Phe Pro Pro Seq. ID NO. 66 Glu Phe Pro Pro Arg Seq. ID NO. 67 Phe Pro Pro Arg Phe Seq. ID NO. 68 Pro Pro Arg Phe Pro Seq. ID NO. 69 Pro Arg Phe Pro Pro Seq. ID NO. 70 Arg Phe Pro Pro Arg Seq. ID NO. 71 Phe Pro Pro Arg Phe Seq. ID NO. 72 Pro Pro Arg Phe Pro

In a preferred embodiment [AA] consists of a penta-peptide as specified in column I of table 2.

In a preferred embodiment [AA] consists of a penta-peptide selected from the group consisting of Arg Arg Arg Pro Arg (SEQ ID NO. 38); Arg Pro Pro Tyr Leu (Seq. ID NO. 42); Pro Tyr Leu Pro Arg (Seq. ID NO. 44); and Tyr Leu Pro Arg Pro (SEQ ID NO. 45).

In a further embodiment the oligopeptide consists of at most 15, preferably at most 10, more preferably at most 7 amino acids, of which 5 consecutive amino acids are identical to 5 consecutive amino acids of SEQ ID NO.1; Thus in one embodiment of the invention, [AA] comprises 5 consecutive amino acids which are identical to 5 consecutive amino acids of SEQ ID NO.1 and has up to 10 further amino acids (resulting in a total number of 15 amino acids), preferably up to 5 further amino acids (resulting in a total number of 10 amino acids), preferably up to 2 further amino acids (resulting in a total number of 7 amino acids) whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)], wherein aa is a penta-peptide of table 2, and X and Y are further amino acids, m and 0 being numbers from 0 to 10, with the proviso that m+o is ≦10. In a preferred embodiment, aa is selected from the pentapeptide as specified in column 1 of table 2. In a further preferred embodiment m+o is ≦5, more preferably ≦2.

In a preferred embodiment [AA] comprises a penta-peptide as specified in column I of table 2.

In a preferred embodiment [AA] comprises a penta-peptide selected from the group consisting of Arg Arg Arg Pro Arg (SEQ ID NO. 38); Arg Pro Pro Tyr Leu (Seq. ID NO. 42); Pro Tyr Leu Pro Arg (SEQ ID NO. 44) and Tyr Leu Pro Arg Pro (SEQ ID NO. 45).

[AA] Moiety: Hexapapetide

In one embodiment of the invention, [AA] consists of 6 consecutive amino acids, which are identical to 6 consecutive amino acids of SEQ ID NO.1.

TABLE 3 34 hexa-peptides of 6 consecutive amino acids of SEQ ID NO. 1 Column I Seq. ID NO. 73 Arg Arg Arg Pro Arg Pro Seq. ID NO. 74 Arg Arg Pro Arg Pro Pro Seq. ID NO. 75 Arg Pro Arg Pro Pro Tyr Seq. ID NO. 76 Pro Arg Pro Pro Tyr Leu Seq. ID NO. 77 Arg Pro Pro Tyr Leu Pro Seq. ID No. 78 Pro Pro Tyr Leu Pro Arg Seq. ID NO. 79 Pro Tyr Leu Pro Arg Pro Seq. ID NO. 80 Tyr Leu Pro Arg Pro Arg Seq. ID NO. 81 Leu Pro Arg Pro Arg Pro Seq. ID No. 82 Pro Arg Pro Arg Pro Pro Column II Seq. ID NO. 83 Arg Pro Arg Pro Pro Pro Seq. ID NO. 84 Pro Arg Pro Pro Pro Phe Seq. ID NO. 85 Arg Pro Pro Pro Phe Phe Seq. ID NO. 86 Pro Pro Pro Phe Phe Pro Seq. ID NO. 87 Pro Pro Phe Phe Pro Pro Seq. ID NO. 88 Pro Phe Phe Pro Pro Arg Seq. ID NO. 89 Phe Phe Pro Pro Arg Leu Seq. ID NO. 90 Phe Pro Pro Arg Leu Pro Seq. ID NO. 91 Pro Pro Arg Leu Pro Pro Seq. ID NO. 92 Pro Arg Leu Pro Pro Arg Column III Seq. ID NO. 93 Arg Leu Pro Pro Arg Ile Seq. ID NO. 94 Leu Pro Pro Arg Ile Pro Seq. ID NO. 95 Pro Pro Arg Ile Pro Pro Seq. ID NO. 96 Pro Arg Ile Pro Pro Glu Seq. ID NO. 97 Arg Ile Pro Pro Glu Phe Seq. ID NO. 98 Ile Pro Pro Glu Phe Pro Seq. ID NO. 99 Pro Pro Glu Phe Pro Pro Seq. ID NO. 100 Pro Glu Phe Pro Pro Arg Seq. ID NO. 101 Glu Phe Pro Pro Arg Phe Seq. ID NO. 102 Phe Pro Pro Arg Phe Pro Seq. ID NO. 103 Pro Pro Arg Phe Pro Pro Seq. ID NO. 104 Pro Arg Phe Pro Pro Arg Seq. ID NO. 105 Arg Phe Pro Pro Arg Phe Seq. ID NO. 106 Phe Pro Pro Arg Phe Pro

In a preferred embodiment [AA] consists of a hexa-peptide as specified in column I of table 3.

In a further embodiment of the oligopeptide consists of at most 15, preferably at most 10, more preferably at most 8 amino acids, of which 6 consecutive amino acids are identical to 6 consecutive amino acids of SEQ ID NO.1; Thus in one embodiment of the invention, [AA] comprises 6 consecutive amino acids which are identical to 6 consecutive amino acids of SEQ ID NO.1 and has up to 9 further amino acids (resulting in a total number of 15 amino acids), preferably up to 5 further amino acids (resulting in a total number of 10 amino acids), preferably up to 2 further amino acids (resulting in a total number of 8 amino acids) whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)], wherein aa is a hexa-peptide of table 3, and X and Yare further amino acids, m and 0 being numbers from 0 to 9, with the proviso that m+o is ≦9. In a preferred embodiment, aa is selected from the hexapeptide as specified in column 1 of table 3. In a further preferred embodiment m+o is ≦4, more preferably ≦2.

[AA] Moiety: Heptapeptide

In one embodiment of the invention, [AA] consists of 7 consecutive amino acids, which are identical to 7 consecutive amino acids of SEQ ID NO.1.

Table 4 lists these hepta-peptides:

33 hepta-peptides of 7 consecutive amino acids of SEQ ID NO. 1 Seq. ID NO. Column I Seq. ID NO. 107 Arg Arg Arg Pro Arg Pro Pro Seq. ID NO. 108 Arg Arg Pro Arg Pro Pro Tyr Seq. ID NO. 109 Arg Pro Arg Pro Pro Tyr Leu Seq. ID NO. 110 Pro Arg Pro Pro Tyr Leu Pro Seq. ID NO. 111 Arg Pro Pro Tyr Leu Pro Arg Seq. ID NO. 112 Pro Pro Tyr Leu Pro Arg Pro Seq. ID NO. 113 Pro Tyr Leu Pro Arg Pro Arg Seq. ID NO. 114 Tyr Leu Pro Arg Pro Arg Pro Seq. ID NO. 115 Leu Pro Arg Pro Arg Pro Pro Column II Seq. ID NO. 116 Pro Arg Pro Arg Pro Pro Pro Seq. ID NO. 117 Arg Pro Arg Pro Pro Pro Phe Seq. ID NO. 118 Pro Arg Pro Pro Pro Phe Phe Seq. ID NO. 119 Arg Pro Pro Pro Phe Phe Pro Seq. ID NO. 120 Pro Pro Pro Phe Phe Pro Pro Seq. ID NO. 121 Pro Pro Phe Phe Pro Pro Arg Seq. ID NO. 122 Pro Phe Phe Pro Pro Arg Leu Seq. ID NO. 123 Phe Phe Pro Pro Arg Leu Pro Seq. ID NO. 124 Phe Pro Pro Arg Leu Pro Pro Column III Seq. ID NO. 125 Pro Prro Arg Leu Pro Pro Arg Seq. ID NO. 126 Pro Arg Leu Pro Pro Arg Ile Seq. ID NO. 127 Arg Leu Pro Pro Arg Ile Pro Seq. ID NO. 128 Leu Pro Pro Arg Ile Pro Pro Seq. ID NO. 129 Pro Pro Arg Ile Pro Pro Glu Seq. ID NO. 130 Pro Arg Ile Pro Pro Glu Phe Seq. ID NO. 131 Arg Ile Pro Pro Glu Phe Pro Seq. ID NO. 132 Ile Pro Pro Glu Phe Pro Pro Seq. ID NO. 133 Pro Pro Glu Phe Pro Pro Arg Seq. ID NO. 134 Pro Glu Phe Pro Pro Arg Phe Seq. ID NO. 135 Glu Phe Pro Pro Arg Phe Pro Seq. ID NO. 136 Phe Pro Pro Arg Phe Pro Pro Seq. ID No. 137 Pro Pro Arg Phe Pro Pro Arg Seq. ID NO. 138 Pro Arg Phe Pro Pro Arg Phe Seq. ID NO. 139 Arg Phe Pro Pro Arg Phe Pro

In a preferred embodiment [AA] consists of a heptapeptide as specified in column I of table 4.

In a further embodiment the oligopeptide consists of at most 15, preferably at most 10, more preferably at most 9 amino acids, of which at least 7 consecutive amino acids are identical to 7 consecutive amino acids of SEQ ID NO.1. Thus in one embodiment of the invention, [AA] comprises 7 consecutive amino acids which are identical to 7 consecutive amino acids of SEQ ID NO.1 and has up to 8 further amino acids (resulting in a total number of 15 amino acids), preferably up to 3 further amino acids (resulting in a total number of 10 amino acids), more preferably up to 2 further amino acid (resulting in a total number of 9 amino acids), whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)], wherein aa is a hepta-peptide of table 4 and X and Y are further amino acids, m and 0 being numbers from 0 to 8, with the proviso that m+o is ≦8. In a preferred embodiment, aa is selected from the heptapeptides as specified in column 1 of table 4. In a further preferred embodiment m+o is ≦3, preferably =2.

[AA] Moiety: Octapeptide

In one embodiment of the invention, [AA] consists of 8 consecutive amino acids, which are identical to 8 consecutive amino acids of SEQ ID NO.1.

Table 5 lists these octa-peptides:

32 octa-peptides of 8 consecutive amino acids of SEQ ID NO. 1 Seq. ID NO. Column I Seq. ID  Arg Arg Arg Pro Arg Pro Pro Tyr NO. 140 Seq. ID  Arg Arg Pro Arg Pro Pro Tyr Leu NO. 141 Seq. ID  Arg Pro Arg Pro Pro Tyr Leu Pro NO. 142 Seq. ID  Pro Arg Pro Pro Tyr Leu Pro Arg NO. 143 Seq. ID  Arg Pro Pro Tyr Leu Pro Arg Pro NO. 144 Seq. ID  Pro Pro Tyr Leu Pro Arg Pro Arg NO. 145 Seq. ID  Pro Tyr Leu Pro Arg Pro Arg Pro NO. 146 Seq. ID  Tyr Leu Pro Arg Pro Arg Pro Pro NO. 147 Column II Seq. ID  Leu Pro Arg Pro Arg Pro Pro Pro NO. 148 Seq. ID  Pro Arg Pro Arg Pro Pro Pro Phe NO. 149 Seq. ID  Arg Pro Arg Pro Pro Pro Phe Phe NO. 150 Seq. ID  Pro Arg Pro Pro Pro Phe Phe Pro NO. 151 Seq. ID  Arg Pro Pro Pro Phe Phe Pro Pro NO. 152 Seq. ID  Pro Pro Pro Phe Phe Pro Pro Arg NO. 153 Seq. ID  Pro Pro Phe Phe Pro Pro Arg Leu NO. 154 Seq. ID  Pro Phe Phe Pro Pro Arg Leu Pro NO. 155 Seq. ID  Phe Phe Pro Pro Arg Leu Pro Pro NO. 156 Seq. ID  Phe Pro Pro Arg Leu Pro Pro Arg NO. 157 Seq. ID  Pro Pro Arg Leu Pro Pro Arg Ile NO. 158 Seq. ID  Pro Arg Leu Pro Pro Arg Ile Pro NO. 159 Seq. ID  Arg Leu Pro Pro Arg Ile Pro Pro NO. 160 Seq. ID  Leu Pro Pro Arg Ile Pro Pro Glu NO. 161 Seq. ID  Pro Pro Arg Ile Pro Pro Glu Phe NO. 162 Seq. ID  Pro Arg Ile Pro Pro Glu Phe Pro NO. 163 Seq. ID  Arg Ile Pro Pro Glu Phe Pro Pro NO. 164 Seq. ID  Ile Pro Pro Glu Phe Pro Pro Arg NO. 165 Seq. ID  Pro Pro Glu Phe Pro Pro Arg Phe NO. 166 Seq. ID  Pro Glu Phe Pro Pro Arg Phe Pro NO. 167 Seq. ID  Glu Phe Pro Pro Arg Phe Pro Pro NO. 168 Seq. ID  Phe Pro Pro Arg Phe Pro Pro Arg NO. 169 Seq. ID  Pro Pro Arg Phe Pro Pro Arg Phe NO. 170 Seq. ID  Pro Arg Phe Pro Pro Arg Phe Pro NO. 171

In a preferred embodiment [AA] consists of an octapeptide as specified in column 1 of table 5. In a further embodiment the oligopeptide consists of at most 15, preferably at most 10 amino acids, of which at least 8 consecutive amino acids are identical to 8 consecutive amino acids of SEQ ID NO.1. Thus in one embodiment of the invention, [AA] comprises 8 consecutive amino acids which are identical to 8 consecutive amino acids of SEQ ID NO.1 and has up to 7 further amino acids (resulting in a total number of 15 amino acids), preferably up to 2 further amino acids (resulting in a total number of 10 amino acids), whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)], wherein aa is a octa-peptide of table 5 and X and Y are further amino acids, m and 0 being numbers from 0 to 7, with the proviso that m+o is ≦7. In a preferred embodiment, aa is selected from the octapeptides as specified in column I of table 5. In a further preferred embodiment m+o is ≦2.

[AA] Moiety: Nonapeptide

In one embodiment of the invention, [AA] consists of 9 consecutive amino acids, which are identical to 9 consecutive amino acids of SEQ ID NO.1.

Table 6 list these nona-peptides:

31 nona peptides of 9 consecutive amino acids of SEQ ID NO. 1 Seq.   ID NO. Column I Seq. ID  Arg Arg Arg Pro Arg Pro Pro Tyr Leu NO. 172 Seq. ID  Arg Arg Pro Arg Pro Pro Tyr Leu Pro NO. 173 Seq. ID  Arg Pro Arg Pro Pro Tyr Leu Pro Arg NO. 174 Seq. ID  Pro Arg Pro Pro Tyr Leu Pro Arg Pro NO. 175 Seq. ID  Arg Pro Pro Tyr Leu Pro Arg Pro Arg NO. 176 Seq. ID  Pro Pro Tyr Leu Pro Arg Pro Arg Pro NO. 177 Seq. ID  Pro Tyr Leu Pro Arg Pro Arg Pro Pro NO. 178 Column II Seq. ID  Tyr Leu Pro Arg Pro Arg Pro Pro Pro NO. 179 Seq. ID  Leu Pro Arg Pro Arg Pro Pro Pro Phe NO. 180 Seq. ID  Pro Arg Pro Arg Pro Pro Pro Phe Phe NO. 181 Seq. ID  Arg Pro Arg Pro Pro Pro Phe Phe Pro NO. 182 Seq. ID  Pro Arg Pro Pro Pro Phe Phe Pro Pro NO. 183 Seq. ID  Arg Pro Pro Pro Phe Phe Pro Pro Arg NO. 184 Seq. ID  Pro Pro Pro Phe Phe Pro Pro Arg Leu NO. 185 Seq. ID  Pro Pro Phe Phe Pro Pro Arg Leu Pro NO. 186 Seq. ID  Pro Phe Phe Pro Pro Arg Leu Pro Pro NO. 187 Seq. ID  Phe Phe Pro Pro Arg Leu Pro Pro Arg No. 188 Seq. ID  Phe Pro Pro Arg Leu Pro Pro Arg Ile No. 189 Seq. ID  Pro Pro Arg Leu Pro Pro Arg Ile Pro NO. 190 Seq. ID  Pro Arg Leu Pro Pro Arg Ile Pro Pro NO. 191 Seq. ID  Arg Leu Pro Pro Arg Ile Pro Pro Glu NO. 192 Seq. ID  Leu Pro Pro Arg Ile Pro Pro Glu Phe NO. 193 Seq. ID  Pro Pro Arg Ile Pro Pro Glu Phe Pro No. 194 Seq. ID  Pro Arg Ile Pro Pro Glu Phe Pro Pro NO. 195 Seq. ID  Arg Ile Pro Pro Glu Phe Pro Pro Arg No. 196 Seq. ID  Ile Pro Pro Glu Phe Pro Pro Arg Phe No. 197 Seq. ID  Pro Pro Glu Phe Pro Pro Arg Phe Pro NO. 198 Seq. ID  Pro Glu Phe Pro Pro Arg Phe Pro Pro NO. 199 Seq. ID  Glu Phe Pro Pro Arg Phe Pro Pro Arg NO. 200 Seq. ID  Phe Pro Pro Arg Phe Pro Pro Arg Phe No. 201 Seq. ID  Pro Pro Arg Phe Pro Pro Arg Phe Pro NO. 202

In a preferred embodiment [AA] consists of a nona-peptide as specified in column I of table 6.

In a further embodiment the oligopeptide consists of at most 15, preferably at most 10 amino acids, of which at least 9 consecutive amino acids are identical to 9 consecutive amino acids of SEQ ID NO.1. Thus in one embodiment of the invention, [AA] comprises 9 consecutive amino acids which are identical to 9 consecutive amino acids of SEQ ID NO.1 and has up to 6 further amino acids (resulting in a total number of 15 amino acids), preferably up to 1 further amino acid (resulting in a total number of 10 amino acids), whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)], wherein aa is a nona-peptide of table 9 and X and Y are further amino acids, m and 0 being numbers from 0 to 5, with the proviso that m+o is ≦5. In a preferred embodiment, aa is selected from the nonapeptides as specified in column I of table 6. In a further preferred embodiment m+o is =1.

[AA] Moiety: Decapeptide

In one embodiment of the invention, [AA] consists of 10 consecutive amino acids, which are identical to 10 consecutive amino acids of SEQ ID NO.1.

Table 7 list these deca-peptides:

30 deca peptides of 10 consecutive amino acids of SEQ ID NO. 1 SEQ ID NO. Column I SEQ ID Arg Arg Arg Pro Arg Pro Pro Tyr Leu  NO. 203 Pro SEQ ID Arg Arg Pro Arg Pro Pro Tyr Leu Pro  NO. 204 Arg SEQ ID Arg Pro Arg Pro Pro Tyr Leu Pro Arg  NO. 205 Pro SEQ ID Pro Arg Pro Pro Tyr Leu Pro Arg Pro  NO. 206 Arg SEQ ID Arg Pro Pro Tyr Leu Pro Arg Pro Arg  NO. 207 Pro SEQ ID Pro Pro Tyr Leu Pro Arg Pro Arg Pro  NO. 208 Pro Column II SEQ ID Pro Tyr Leu Pro Arg Pro Arg Pro Pro  NO. 209 Pro SEQ ID Tyr Leu Pro Arg Pro Arg Pro Pro Pro  NO. 210 Phe SEQ ID Leu Pro Arg Pro Arg Pro Pro Pro Phe  NO. 211 Phe SEQ ID Pro Arg Pro Arg Pro Pro Pro Phe Phe  NO. 212 Pro SEQ ID Arg Pro Arg Pro Pro Pro Phe Phe Pro  NO. 213 Pro SEQ ID Pro Arg Pro Pro Pro Phe Phe Pro Pro  NO. 214 Arg SEQ ID Arg Pro Pro Pro Phe Phe Pro Pro Arg  NO. 215 Leu SEQ ID Pro Pro Pro Phe Phe Pro Pro Arg Leu  NO. 216 Pro SEQ ID Pro Pro Phe Phe Pro Pro Arg Leu Pro  NO. 217 Pro SEQ ID Pro Phe Phe Pro Pro Arg Leu Pro Pro  NO. 218 Arg SEQ ID Phe Phe Pro Pro Arg Leu Pro Pro Arg  NO. 219 Ile SEQ ID Phe Pro Pro Arg Leu Pro Pro Arg Ile  NO. 220 Pro SEQ ID Pro Pro Arg Leu Pro Pro Arg Ile Pro  NO. 221 Pro SEQ ID Pro Arg Leu Pro Pro Arg Ile Pro Pro  NO. 222 Glu SEQ ID Arg Leu Pro Pro Arg Ile Pro Pro Glu  NO. 223 Phe SEQ ID Leu Pro Pro Arg Ile Pro Pro Glu Phe  NO. 224 Pro SEQ ID Pro Pro Arg Ile Pro Pro Glu Phe Pro  NO. 225 Pro SEQ ID Pro Arg Ile Pro Pro Glu Phe Pro Pro  NO. 226 Arg SEQ ID Arg Ile Pro Pro Glu Phe Pro Pro Arg  NO. 227 Phe SEQ ID Ile Pro Pro Glu Phe Pro Pro Arg Phe  NO. 228 Pro SEQ ID Pro Pro Glu Phe Pro Pro Arg Phe Pro  NO. 229 Pro SEQ ID Pro Glu Phe Pro Pro Arg Phe Pro Pro  NO. 230 Arg SEQ ID Glu Phe Pro Pro Arg Phe Pro Pro Arg  NO. 231 Phe SEQ ID Phe Pro Pro Arg Phe Pro Pro Arg Phe  NO. 232 Pro

In a preferred embodiment [AA] consists of a deca-peptide as specified in column I of table 7.

In a further embodiment the oligopeptide consists of at most 15, preferably at most 12 amino acids, of which at least 10 consecutive amino acids are identical to 10 consecutive amino acids of SEQ ID NO.1. Thus in one embodiment of the invention, [AA] comprises 10 consecutive amino acids which are identical to 10 consecutive amino acids of SEQ ID NO.1 and has up to 4 further amino acids (resulting in a total number of 15 amino acids), preferably up to 2 further amino acids (resulting in a total number of 12 amino acids), whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)], wherein aa is a deca-peptide of table 7 and X and Y are further amino acids, m and 0 being numbers from 0 to 5, with the proviso that m+o is ≦5.

In a preferred embodiment, aa is selected from the decapeptides as specified in column 1 of table 7. In a further preferred embodiment m+o is ≦2.

[AA] Moiety: Undecapeptide

In one embodiment of the invention, [AA] consists of 11 consecutive amino acids, which are identical to 11 consecutive amino acids of SEQ ID NO.1.

Table 8 lists these undeca-peptides:

29 undeca-peptides of 11 consecutive amino acids of SEQ ID NO. 1 Seq. ID NO. Column I Seq. ID Arg Arg Arg Pro Arg Pro Pro Tyr Leu  NO. 233 Pro Arg Seq. ID Arg Arg Pro Arg Pro Pro Tyr Leu Pro  NO. 234 Arg Pro Seq. ID Arg Pro Arg Pro Pro Tyr Leu Pro Arg  NO. 235 Pro Arg Seq. ID Pro Arg Pro Pro Tyr Leu Pro Arg Pro  NO. 236 Arg Pro Seq. ID Arg Pro Pro Tyr Leu Pro Arg Pro Arg  NO. 237 Pro Pro Column II SEQ ID Pro Pro Tyr Leu Pro Arg Pro Arg Pro  NO. 238 Pro Pro SEQ ID Pro Tyr Leu Pro Arg Pro Arg Pro Pro  NO. 239 Pro Phe SEQ ID Tyr Leu Pro Arg Pro Arg Pro Pro Pro  NO. 240 Phe Phe Seq. ID Leu Pro Arg Pro Arg Pro Pro Pro Phe  NO. 241 Phe Pro SEQ ID Pro Arg Pro Arg Pro Pro Pro Phe Phe  NO. 242 Pro Pro SEQ ID Arg Pro Arg Pro Pro Pro Phe Phe Pro  NO. 243 Pro Arg Seq. ID Pro Arg Pro Pro Pro Phe Phe Pro Pro  NO. 244 Arg Leu SEQ ID Arg Pro Pro Pro Phe Phe Pro Pro Arg  NO. 245 Leu Pro SEQ ID Pro Pro Pro Phe Phe Pro Pro Arg Leu  NO. 246 Pro Pro SEQ ID Pro Pro Phe Phe Pro Pro Arg Leu Pro  NO. 247 Pro Arg SEQ ID Pro Phe Phe Pro Pro Arg Leu Pro Pro  NO. 248 Arg Ile SEQ ID Phe Phe Pro Pro Arg Leu Pro Pro Arg  NO. 249 Ile Pro SEQ ID Phe Pro Pro Arg Leu Pro Pro Arg Ile  NO. 250 Pro Pro Seq. ID Pro Pro Arg Leu Pro Pro Arg Ile Pro  NO. 251 Pro Glu Seq. ID Pro Arg Leu Pro Pro Arg Ile Pro Pro  NO. 252 Glu Phe SEQ ID Arg Leu Pro Pro Arg Ile Pro Pro Glu  NO. 253 Phe Pro SEQ ID Leu Pro Pro Arg Ile Pro Pro Glu Phe  NO. 254 Pro Pro SEQ ID Pro Pro Arg Ile Pro Pro Glu Phe Pro  NO. 255 Pro Arg SEQ ID Pro Arg Ile Pro Pro Glu Phe Pro Pro  NO. 256 Arg Phe SEQ ID Arg Ile Pro Pro Glu Phe Pro Pro Arg  NO. 257 Phe Pro SEQ ID Ile Pro Pro Glu Phe Pro Pro Arg Phe  NO. 258 Pro Pro SEQ ID Pro Pro Glu Phe Pro Pro Arg Phe Pro  NO. 259 Pro Arg SEQ ID Pro Glu Phe Pro Pro Arg Phe Pro Pro  NO. 260 Arg Phe SEQ ID Glu Phe Pro Pro Arg Phe Pro Pro Arg  NO. 261 Phe Pro

In a preferred embodiment [AA] consists of an undeca-peptide as specified in column I of table 8.

In a further embodiment the oligopeptide consists of at most 15, preferably at most 12 amino acids, of which at least 11 consecutive amino acids are identical to 11 consecutive amino acids of SEQ ID NO.1. Thus in one embodiment of the invention, [AA] comprises 11 consecutive amino acids which are identical to 11 consecutive amino acids of SEQ ID NO. 1 and has up to 4 further amino acids (resulting in a total number of 15 amino acids), preferably up to 1 further amino acids (resulting in a total number of 12 amino acids), whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)], wherein aa is an undeca-peptide of table 8 and X and Yare further amino acids, m and 0 being numbers from 0 to 4, with the proviso that m+o is ≦4. In a preferred embodiment, aa is selected from the undecapeptides as specified in column I of table 8. In a further preferred embodiment m+o is =1.

[AA] Moiety: Dodecapeptide

In one embodiment of the invention, [AA] consists of 12 consecutive amino acids, which are identical to 12 consecutive amino acids of SEQ ID NO. 1.

Table 9 lists these dodeca-peptides:

28 dodeca-peptides of 12 consecutive amino acids of SEQ ID No. 1 SEQ ID NO. Column I SEQ ID NO. 262 Arg Arg Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro SEQ ID NO. 263 Arg Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg SEQ ID NO. 264 Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro SEQ ID NO. 265 Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Column II SEQ ID NO. 266 Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Seq. ID NO. 267 Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe SEQ ID NO. 268 Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe SEQ ID NO. 269 Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro SEQ ID NO. 270 Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro SEQ ID NO. 271 Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg SEQ ID NO. 272 Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu SEQ ID NO. 273 Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Seq. ID NO. 274 Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro SEQ ID NO. 275 Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg SEQ ID NO. 276 Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile SEQ ID NO. 277 Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro SEQ ID NO. 278 Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro SEQ ID NO. 279 Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu SEQ ID NO. 280 Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe SEQ ID NO. 281 Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro SEQ ID NO. 282 Arg Leu Pro Pro Arg Ile Pro Pro Giu Phe Pro Pro SEQ ID NO. 283 Leu Pro Pro Arg lie Pro Pro Glu Phe Pro Pro Arg SEQ ID NO. 284 Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe SEQ ID NO. 285 Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro SEQ ID NO. 286 Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro SEQ ID NO. 287 Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Seq. ID NO. 288 Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Phe SEQ ID NO. 289 Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Phe Pro

In a preferred embodiment [AA) consists of a dodeca-peptide as specified in column I of table 9.

In a further embodiment the oligopeptide consists of at most 15, of which at least 12 consecutive amino acids are identical to 12 consecutive amino acids of SEQ ID NO. 1. Thus in one embodiment of the invention, [AA] comprises 12 consecutive amino acids which are identical to 12 consecutive amino acids of SEQ ID NO.1 and has up to 3 further amino acids (resulting in a total number of 15 amino acids), preferably up to 2 further amino acids (resulting in a total number of 14 amino acids), more preferably up to 1 further amino acid (resulting in a total number of 13 amino acids), whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)), wherein aa is a dodeca-peptide of table 9 and X and Y are further amino acids, m and 0 being numbers from a to 3, with the proviso that m+o is ≦3. In a preferred embodiment, aa is selected from the dodecapeptides as specified in column I of table 9. In a further preferred embodiment m+o is ≦2, preferably =1.

[AA] Moiety: Tridecapeptide

In one embodiment of the invention, [AA] consists of 13 consecutive amino acids, which are identical to 13 consecutive amino acids of SEQ ID NO.1.

Table 10 lists these trideca-peptides:

27 trideca peptides of 13 consecutive amino acids of SEQ ID NO. 1 SEQ ID NO. Column I Seq. ID NO. 290 Arg Arg Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg SEQ ID NO. 291 Arg Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro SEQ ID NO. 292 Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Column II Seq. ID NO. 293 Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Seq. ID NO. 294 Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Seq. ID NO. 285 Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Seq. ID NO. 296 Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Seq. ID NO. 297 Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Seq. ID NO. 298 Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Seq. ID NO. 299 Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Seq. ID NO. 300 Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Seq. ID NO. 301 Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Seq. ID NO. 302 Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Seq. ID NO. 303 Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Seq. ID NO. 304 Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Seq. ID NO. 305 Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Seq. ID NO. 306 Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Seq. ID NO. 307 Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Seq. ID NO. 308 Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Seq. ID NO. 309 Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Seq. ID NO. 310 Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Seq. ID NO. 311 Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Seq. ID NO. 312 Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Seq. ID NO. 313 Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Seq. ID NO. 314 Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Seq. ID NO. 315 Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Phe Seq. ID NO. 316 Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Phe Pro

In a preferred embodiment [AA] consists of a trideca-peptide as specified in column I of table 10.

In a further embodiment the oligopeptide consists of at most 15, preferably at most 14 amino acids, of which at least 13 consecutive amino acids are identical to 13 consecutive amino acids of SEQ ID NO.1. Thus in one embodiment of the invention, [AA] comprises 13 consecutive amino acids which are identical to 13 consecutive amino acids of SEQ ID NO.1 and has up to 2 further amino acids (resulting in a total number of 15 amino acids), preferably up to 1 further amino acids (resulting in a total number of 14 amino acids), whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)] wherein aa is a trideca-peptide of table 10 and X and Yare further amino acids, m and o being numbers from 0 to 2, with the proviso that m+o is ≦2. In a preferred embodiment, aa is selected from the trdecapeptides as specified in column I of table 10. In a further preferred embodiment m+o is =1.

[AA] Moiety: Tetradecapeptide

In one embodiment of the invention, [AA] consists of 14 consecutive amino acids, which are identical to 14 consecutive amino acids of SEQ ID NO.1.

Table 11 lists these tetradeca-peptides:

26 tetradeca peptides of 14 consecutive amino acids of SEQ ID NO. 1 SEQ ID NO. Column I Seq. ID No. 317 Arg Arg Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Seq. ID NO. 318 Arg Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Column II Seq. ID NO. 319 Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Seq. ID NO. 320 Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Seq. ID NO. 321 Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Seq. ID NO. 322 Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Seq. ID NO. 323 Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Seq. ID NO. 324 Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Seq. ID NO. 325 Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Seq. ID NO. 326 Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Seq. ID NO. 327 Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Seq. ID NO. 328 Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg He Seq. ID NO. 329 Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg He Pro Seq. ID NO. 330 Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Seq. ID NO. 331 Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Seq. ID NO. 332 Phe Phe Pro Pro Arg Leu Pro Pro Arg He Pro Pro Glu Phe Seq. ID NO. 333 Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Seq. ID NO. 334 Pro Arg Leu Pro Pro Arg He Pro Pro Glu Phe Pro Pro Arg Seq. ID NO. 335 Arg Leu Pro Pro Arg He Pro Pro Glu Phe Pro Pro Arg Phe Seq. ID NO. 336 Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Seq. ID NO. 337 Pro Pro Arg He Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Seq. ID NO. 338 Pro Arg He Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg SEQ ID NO. 339 Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Phe Seq. ID NO. 340 Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Phe Pro

In a preferred embodiment [AA] consists of a tetradeca-peptide as specified in column I of table 11.

In a further embodiment the oligopeptide consists of at most 15, of which at least 14 consecutive amino acids are identical to 14 consecutive amino acids of SEQ ID NO. 1. Thus in one embodiment of the invention, [AA] comprises 14 consecutive amino acids which are identical to 14 consecutive amino acids of SEQ ID NO.1 and has up to 1 further amino acids (resulting in a total number of 15 amino acids), whereas the further amino acids need not be identical to or even present in SEQ ID NO.1.

In this embodiment [AA] is thus [X_(m)-aa-Y_(o)], wherein aa is a tetradeca-peptide of table 1 and X and Y are further amino acids, m and 0 being numbers from a to 1, with the proviso that m+o is =1. In a preferred embodiment, aa is selected from the tetradeca-peptides as specified in column I of table 11.

[AA] Moiety: Pentadecapeptide

In one embodiment of the invention, [AA] consists of 15 consecutive amino acids, which are identical to 15 consecutive amino acids of SEQ ID NO.1.

Table 12 lists these pentadeca peptides:

25 pentadeca-peptides of 15 consecutive amino acids of SEQ ID NO. 1 SEQ ID NO. Column I SEQ ID NO. 341 Arg Arg Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Column II SEQ ID NO. 342 Arg Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Seq. ID NO. 343 Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe SEQ ID NO. 344 Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe SEQ ID NO. 345 Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro SEQ ID NO. 346 Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro SEQ ID NO. 347 Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg SEQ ID NO. 348 Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu SEQ ID NO. 349 Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro SEQ ID NO. 350 Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro SEQ ID NO. 351 Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg SEQ ID NO. 352 Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile SEQ ID NO. 353 Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro SEQ ID NO. 354 Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Seq. ID NO. 355 Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu SEQ ID NO. 356 Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe SEQ ID NO. 357 Phe Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro SEQ ID NO. 358 Phe Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro SEQ ID NO. 359 Pro Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg SEQ ID NO. 360 Pro Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe SEQ ID NO. 361 Arg Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro SEQ ID NO. 362 Leu Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro SEQ ID NO. 363 Pro Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg SEQ ID NO. 364 Pro Arg Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Phe SEQ ID NO. 365 Ar~ Ile Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Phe Pro

In a preferred embodiment [AA] consists of the pentadeca-peptide as specified in column I of table 12.

[AA] Moiety: Hexapeptides

In an embodiment [AA] comprises at least 6 amino acids, of which 4, preferably 5, more preferably 6 are identical compared to 6 consecutive amino acids of SEQ ID NO.1. Any possible 6 consecutive amino acids of SEQ ID NO.1 are listed in Table 3.

Thus in this embodiment of the invention, [AA] comprises at least 6 amino acids, of which at least 66.6%, preferably at least 83.3%, preferably 100% are identical to 6 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 6 amino acids, of which 4 amino acids, preferably 5 amino acids are identical compared to 6 consecutive amino acids of SEQ ID NO.1 and the position of the 4, respective 5 identical amino acids is also identical when compared to the respective positions of the 6 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 6 amino acids, of which at least 66.6%, preferably at least 83.3% are identical to 6 consecutive amino acids of SEQ ID NO.1 and the position of the 4, respective 5 identical amino acids is also identical when compared to the respective positions of the 6 amino acids of SEQ ID NO.1.

The following chart illustrates this embodiment of the invention. X and Yare further amino acids.

Position No. 1 2 3 4 5 6 SEQ Arg Arg Arg Pro Arg Pro ID NO. 1 [AAI Arg X Arg Y Arg Pro [AA] Arg Arg Arg Y Arg Pro

In a preferred embodiment [AA] comprises at least 6 amino acids, of which 4, preferably 5 are identical to 6 consecutive amino acids of column I of table 3.

In a further embodiment [AA] consists of 6 amino acids, of which 4, preferably 5, more preferably 6 are identical compared to 6 consecutive amino acids of SEQ ID NO.1. Any possible 6 consecutive amino acids of SEQ ID NO.1 are listed in Table 3.

Thus in this embodiment of the invention, [AA] consists of 6 amino acids, of which at least 66.6%, preferably at least 83.3%, more preferably 100% are identical to 6 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 6 amino acids, of which 4 amino acids, preferably 5 amino acids are identical compared to 6 consecutive amino acids of SEQ ID NO.1 and the position of the 4, respective 5 identical amino acids is also identical when compared to the respective position of the 6 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of least 6 amino acids, of which 4, preferably 5 are identical to 6 consecutive amino acids of column I of table 3.

In a further embodiment [AA] consists of at most 15, preferably at most 10, more preferably at most 8 amino acids, of which 4 amino acids, preferably 5 amino acids, more preferably 6, are identical to 6 consecutive amino acids of SEQ ID NO.1.

In a further embodiment [AA] consists of at most 15, preferably at most 10, more preferably at most 8 amino acids, of which 4 amino acids, preferably 5 amino acids, are identical to 6 consecutive amino acids of SEQ ID NO.1 and the position of the 4, respective 5 amino acids is identical to the positions of respective amino acids of the 6 amino acids of SEQ ID NO. 1. In this embodiment of the invention, also the position of the 4, respective 5 amino acids is identical when compared to the respective positions of 6 consecutive amino acids of SEQ ID NO.1.

[AA] Moiety: Heptapeptides

In a further embodiment [AA] comprises at least 7 amino acids, of which 5, preferably 6, more preferably 7 are identical compared to 7 consecutive amino acids of SEQ ID NO.1. Any possible 7 consecutive amino acids of SEQ ID NO.1 are listed in Table 4.

Thus in this embodiment of the invention, [AA] comprises at least 7 amino acids, of which at least 71.4%, preferably at least 85.7%, preferably 100% are identical to 7 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 7 amino acids, of which 5 amino acids, preferably 6 amino acids are identical compared to 7 consecutive amino acids of SEQ ID NO.1 and the position of the 5, respective 6 identical amino acids is also identical when compared to the respective positions of the 7 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 7 amino acids, of which at least 71.4%, preferably at least 85.7% are identical to 7 consecutive amino acids of SEQ ID NO.1 and the position of the 5, respective 6 identical amino acids is also identical when compared to the respective positions of the 7 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 7 amino acids, of which 5, preferably 6 are identical to 7 consecutive amino acids of column I of table 4.

In a further embodiment [AA] consists of 7 amino acids, of which 5, preferably 6, preferably 7 are identical compared to 7 consecutive amino acids of SEQ ID NO.1. Any possible 7 consecutive amino acids of SEQ ID NO.1 are listed in table 4.

Thus in this embodiment of the invention, [AA] consists of 7 amino acids, of which at least 71.4%, preferably at least 85.7%, preferably 100% are identical to 7 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 7 amino acids, of which 5 amino acids, preferably 6 amino acids are identical compared to 7 consecutive amino acids of SEQ ID NO.1 and the position of the 5, respective 6 identical amino acids is also identical when compared to the respective position of the 7 amino acids of SEQ ID NO.1.

In a preferred embodiment (AA] consists of least 7 amino acids, of which 5, preferably 6 are identical to 7 consecutive amino acids of column I of table 4.

In a further embodiment [AA] consists of at most 15, preferably at most 10, more preferably at most 8 amino acids, of which 5, preferably 6, preferably 7 amino acids, are identical to 7 consecutive amino acids of SEQ ID NO.1.

In a further embodiment [AA] consists of at most 15, preferably at most 10, more preferably at most 8 amino acids, of which 5 amino acids, preferably 6 amino acids, are identical to 7 consecutive amino acids of SEQ ID NO.1 and the position of the 5, respective 6 amino acids is identical to the positions of respective amino acids of the 7 amino acids of SEQ ID no. 1. In this embodiment of the invention, also the position of the 5, respective 6 amino acids is identical when compared to the respective positions of 7 consecutive amino acids of SEQ ID NO.1.

[AA] Moiety: Octapeptides

In a further embodiment [AA] comprises at least 8 amino acids, of which 6, preferably 7, preferably 8 are identical compared to 8 consecutive amino acids of SEQ ID NO.1. Any possible 8 consecutive amino acids of SEQ ID NO.1 are listed in Table 5.

Thus in this embodiment of the invention, [AA] comprises at least 8 amino acids, of which at least 75%, preferably at least 87.5%, preferably 100% are identical to 8 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 8 amino acids, of which 6 amino acids, preferably 7 amino acids are identical compared to 8 consecutive amino acids of SEQ ID NO. 1 and the position of the 6, respective 7 identical amino acids is also identical when compared to the respective positions of the 8 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 8 amino acids, of which at least 75%, preferably at least 87.5% are identical to 8 consecutive amino acids of SEQ ID NO.1 and the position of the 6, respective 7 identical amino acids is also identical when compared to the respective positions of the 8 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 8 amino acids, of which 6, preferably 7 are identical to 8 consecutive amino acids of column I of table 5.

In a further embodiment [AA] consists of 8 amino acids, of which 6, preferably 7, preferably 8 are identical compared to 8 consecutive amino acids of SEQ ID NO.1. Any possible 8 consecutive amino acids of SEQ ID NO.1 are listed in table 5.

Thus in this embodiment of the invention, [AA] consists of 8 amino acids, of which at least 75%, preferably at least 87.5%, preferably 100% are identical to 8 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 8 amino acids, of which 6 amino acids, preferably 7 amino acids are identical compared to 8 consecutive amino acids of SEQ ID NO.1 and the position of the 6, respective 7 identical amino acids is also identical when compared to the respective position of the 8 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of least 8 amino acids, of which 6, preferably 7 are identical to 8 consecutive amino acids of column I of table 5.

In a further embodiment [AA] consists of at most 15, preferably at most 10, more preferably at most 9 amino acids, of which 6, preferably 7, preferably 8 amino acids, are identical to 8 consecutive amino acids of SEQ ID NO.1.

In a further embodiment [AA] consists of at most 15, preferably at most 10, more preferably at most 9 amino acids, of which 6 amino acids, preferably 7 amino acids, are identical to 8 consecutive amino acids of SEQ ID NO.1 and the position of the 6, respective 7 amino acids is identical to the positions of respective amino acids of the 8 amino acids of SEQ ID no. 1. In this embodiment of the invention, also the position of the 6, respective 7 amino acids is identical when compared to the respective positions of 8 consecutive amino acids of SEQ ID NO.1.

[AA] Moiety: Nonapeptides

In a further embodiment [AA] comprises at least 9 amino acids, of which 6, preferably 7, more preferably 8, more preferably 9 amino acids are identical compared to 9 consecutive amino acids of SEQ ID NO.1. Any possible 9 consecutive amino acids of SEQ ID NO.1 are listed in Table 6.

Thus in this embodiment of the invention, [AA] comprises at least 9 amino acids, of which at least 66.6%, preferably at least 77.7%, more preferably at least 88.8%, more preferably 100% are identical to 9 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 9 amino acids, of which 6 amino acids, preferably 7 amino acids, more preferably 8 amino acids are identical compared to 9 consecutive amino acids of SEQ ID NO.1 and the position of the 6, respective 7 or 8 identical amino acids is also identical when compared to the respective positions of the 9 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 9 amino acids, of which at least 66.6%, preferably at least 77.7%, more preferably at least 88.8% are identical to 9 consecutive amino acids of SEQ ID NO.1 and the position of the 6, respective 7 or 8 identical amino acids is also identical when compared to the respective positions of the 9 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 9 amino acids, of which 6, preferably 7, more preferably 8 are identical to 9 consecutive amino acids of column I of table 6.

In a further embodiment [AA] consists of 9 amino acids, of which 6, preferably 7, more preferably 8, more preferably 9, are identical compared to 9 consecutive amino acids of SEQ ID NO.1. Any possible 9 consecutive amino acids of SEQ ID NO.1 are listed in table 6.

Thus in this embodiment of the invention, [AA] consists of 9 amino acids, of which at least 66.6%, preferably at least 77.7%, more preferably at least 88.8%, more preferably 100% are identical to 9 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 9 amino acids, of which 6 amino acids, preferably 7 amino acids, more preferably 8 amino acids are identical compared to 9 consecutive amino acids of SEQ ID NO.1 and the position of the 6, respective 7 or 8 identical amino acids is also identical when compared to the respective position of the 9 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of least 9 amino acids, of which 6, preferably 7, more preferably 8 are identical to 9 consecutive amino acids of column I of table 6.

In a further embodiment [AA] consists of at most 15, preferably at most 12, more preferably at most 10 amino acids, of which 6, preferably 7, more preferably 8, more preferably 9 amino acids are identical to 9 consecutive amino acids of SEQ ID NO.1.

In a further embodiment [AA] consists of at most 15, preferably at most 12, more preferably at most 10 amino acids, of which 6 amino acids, preferably 7, more preferably 8 amino acids, are identical to 9 consecutive amino acids of SEQ ID NO. 1 and the position of the 6, respective 7 or 8 amino acids is identical to the positions of respective amino acids of the 9 amino acids of SEQ ID NO.1. In this embodiment of the invention, also the position of the 6, respective 7 or 8 amino acids is identical when compared to the respective positions of 9 consecutive amino acids of SEQ ID NO.1.

[AA] Moiety: Decapeptides

In a further embodiment [AA] comprises at least 10 amino acids, of which 7, preferably 8, more preferably 9, more preferably 10 amino acids are identical compared to 10 consecutive amino acids of SEQ ID NO.1. Any possible 10 consecutive amino acids of SEQ ID NO.1 are listed in Table 7.

Thus in this embodiment of the invention, [AA] comprises at least 10 amino acids, of which at least 70%, preferably at least 80%, more preferably at least 90%, more preferably 100% are identical to 10 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 10 amino acids, of which 7 amino acids, preferably 8 amino acids, more preferably 9 amino acids are identical compared to 10 consecutive amino acids of SEQ ID NO.1 and the position of the 7, respective 8 or 9 identical amino acids is also identical when compared to the respective positions of the 10 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 10 amino acids, of which at least 70%, preferably at least 80%, more preferably at least 90% are identical to 10 consecutive amino acids of SEQ ID NO.1 and the position of the 7, respective 8 or 9 identical amino acids is also identical when compared to the respective positions of the 10 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 10 amino acids, of which 7, preferably 8, more preferably 9 are identical to 10 consecutive amino acids of column I of table 7.

In a further embodiment [AA] consists of 10 amino acids, of which 7, preferably 8, more preferably 9, more preferably 10 are identical compared to 10 consecutive amino acids of SEQ ID NO.1. Any possible 10 consecutive amino acids of SEQ ID NO.1 are listed in table 7.

Thus in this embodiment of the invention, [AA] consists of 10 amino acids, of which at least 70%, preferably at least 80%, more preferably at least 90%, more preferably 100% are identical to 10 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 10 amino acids, of which 7 amino acids, preferably 8 amino acids, more preferably 9 amino acids are identical compared to 10 consecutive amino acids of SEQ ID NO.1 and the position of the 7, respective 8 or 9 identical amino acids is also identical when compared to the respective position of the 10 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of least 10 amino acids, of which 7, preferably 8, more preferably 9 are identical to 10 consecutive amino acids of column I of table 7.

In a further embodiment [AA] consists of at most 15, preferably at most 14, more preferably at most 12 amino acids, of which, preferably 8, more preferably 9, more preferably 10 amino acids, are identical to 10 consecutive amino acids of SEQ ID NO. 1.

In a further embodiment [AA] consists of at most 15, preferably at most 14, more preferably at most 12 amino acids, of which 7 amino acids, preferably 8, more preferably 9 amino acids, are identical to 10 consecutive amino acids of SEQ ID NO. 1 and the position of the 7, respective 8 or 9 amino acids is identical to the positions of respective amino acids of the 10 amino acids of SEQ ID NO.1. In this embodiment of the invention, also the position of the 7, respective 8 or 9 amino acids is identical when compared to the respective positions of 10 consecutive amino acids of SEQ ID NO.1.

[AA] Moiety: Undecapeptides

In a further embodiment [AA] comprises at least 11 amino acids, of which 8, preferably 9, more preferably 10, more preferably 11 amino acids are identical compared to 11 consecutive amino acids of SEQ ID NO.1. Any possible 11 consecutive amino acids of SEQ ID NO.1 are listed in Table 8.

Thus in this embodiment of the invention, [AA] comprises at least 11 amino acids, of which at least 72.7%, preferably at least 81.8%, more preferably at least 90.9%, more preferably 100% are identical to 11 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 11 amino acids, of which 8 amino acids, preferably 9 amino acids, more preferably 10 amino acids are identical compared to 11 consecutive amino acids of SEQ ID NO.1 and the position of the 8, respective 9 or 10 identical amino acids is also identical when compared to the respective positions of the 11 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 11 amino acids, of which at least 72.7%, preferably at least 81.8%, more preferably at least 90.9% are identical to 11 consecutive amino acids of SEQ ID NO.1 and the position of the 8, respective 9 or 10 identical amino acids is also identical when compared to the respective positions of the 11 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 11 amino acids, of which 8, preferably 9, more preferably 10 are identical to 11 consecutive amino acids of column I of table 8.

In a further embodiment [AA] consists of 11 amino acids, of which 8, preferably 9, more preferably 10, more preferably 11 are identical compared to 11 consecutive amino acids of SEQ ID NO.1. Any possible 11 consecutive amino acids of SEQ ID NO.1 are listed in table 8.

Thus in this embodiment of the invention, [AA] consists of 11 amino acids, of which at least 72.7%, preferably at least 81.8%, more preferably at least 90.9%, more preferably 100% are identical to 11 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 11 amino acids, of which 8 amino acids, preferably 9 amino acids, more preferably 10 amino acids are identical compared to 11 consecutive amino acids of SEQ ID NO. 1 and the position of the 8, respective 9 or 10 identical amino acids is also identical when compared to the respective position of the 11 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of least 11 amino acids, of which 8, preferably 9, more preferably 10 are identical to 11 consecutive amino acids of column I of table 8.

In a further embodiment [AA] consists of at most 15, preferably at most 14, more preferably at most 12 amino acids, of which 8, preferably 9, more preferably 10, more preferably 11 amino acids, are identical to 11 consecutive amino acids of SEQ ID NO. 1.

In a further embodiment [AA] consists of at most 15, preferably at most 14, more preferably at most 12 amino acids, of which 8 amino acids, preferably 9, more preferably 10 amino acids, are identical to 11 consecutive amino acids of SEQ ID NO. 1 and the position of the 8, respective 9 or 10 amino acids is identical to the positions of respective amino acids of the 11 amino acids of SEQ ID NO.1. In this embodiment of the invention, also the position of the 8, respective 9 or 10 amino acids is identical when compared to the respective positions of 11 consecutive amino acids of SEQ ID NO.1.

[AA] Moiety: Dodecapeptides

In a further embodiment [AA] comprises at least 12 amino acids, of which 8, preferably 9, more preferably 10, most preferably 11, most preferably 12 amino acids are identical compared to 12 consecutive amino acids of SEQ ID NO.1. Any possible 12 consecutive amino acids of SEQ ID NO.1 are listed in Table 9.

Thus in this embodiment of the invention, [AA] comprises at least 12 amino acids, of which at least 66.6%, preferably at least 75%, more preferably at least 83.3%, most preferably at least 91.6%, most preferably 100% are identical to 12 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 12 amino acids, of which 8 amino acids, preferably 9 amino acids, more preferably 10, most preferably 11 amino acids are identical compared to 12 consecutive amino acids of SEQ ID NO. 1 and the position of the 8, respective 9 or 10 or 11 identical amino acids is also identical when compared to the respective positions of the 12 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 12 amino acids, of which at least 66.6%, preferably at least 75%, more preferably at least 83.3%, most preferably at least 91.6% are identical to 12 consecutive amino acids of SEQ ID NO.1 and the position of the 8, respective 9 or 10 or 11 identical amino acids is also identical when compared to the respective positions of the 12 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 12 amino acids, of which 8, preferably 9, more preferably 10, most preferably 11 are identical to 12 consecutive amino acids of column I of table 9.

In a further embodiment [AA] consists of 12 amino acids, of which 8, preferably 9, more preferably 10, most preferably 11, most preferably 12 are identical compared to 12 consecutive amino acids of SEQ ID NO.1. Any possible 12 consecutive amino acids of SEQ ID NO.1 are listed in table 9.

Thus in this embodiment of the invention, [AA] consists of 12 amino acids, of which at least 66.6%, preferably at least 75%, more preferably at least 83.3%, most preferably at least 91.6%, most preferably 100% are identical to 12 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 12 amino acids, of which 8 amino acids, preferably 9 amino acids, more preferably 10 amino acids, most preferably 11 amino acids are identical compared to 12 consecutive amino acids of SEQ ID NO. 1 and the position of the 8, respective 9 or 10 or 11 identical amino acids is also identical when compared to the respective position of the 12 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of least 12 amino acids, of which 8, preferably 9, more preferably 10, most preferably 11 are identical to 12 consecutive amino acids of column I of table 9.

In a further embodiment [AA] consists of at most 15, preferably at most 14, more preferably at most 13 amino acids, of which 8, preferably 9, more preferably 10, most preferably 11, most preferably 12 amino acids, are identical to 12 consecutive amino acids of SEQ ID NO.1.

In a further embodiment [AA] consists of at most 15, preferably at most 14, more preferably at most 13 amino acids, of which 8 amino acids, preferably 9, more preferably 10, most preferably 11 amino acids, are identical to 12 consecutive amino acids of SEQ ID NO.1 and the position of the 8, respective 9 or 10 or 11 amino acids is identical to the positions of respective amino acids of the 12 amino acids of SEQ ID NO.1. In this embodiment of the invention, also the position of the 8, respective 9 or 10 or 11 amino acids is identical when compared to the respective positions of 12 consecutive amino acids of SEQ ID NO.1.

[AA] Moiety: Tridecapeptides

In a further embodiment [AA] comprises at least 13 amino acids, of which 9, preferably 10, more preferably 11, most preferably 12, most preferably 13 amino acids are identical compared to 13 consecutive amino acids of SEQ ID NO.1. Any possible 13 consecutive amino acids of SEQ ID NO.1 are listed in Table 10.

Thus in this embodiment of the invention, [AA] comprises at least 13 amino acids, of which at least 69.2%, preferably at least 76.9%, more preferably at least 84.6%, most preferably at least 92.3%, most preferably 100% are identical to 13 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 13 amino acids, of which 9 amino acids, preferably 10 amino acids, more preferably 11, most preferably 12 amino acids are identical compared to 13 consecutive amino acids of SEQ ID NO.1 and the position of the 9, respective 10, 11 or 12 identical amino acids is also identical when compared to the respective positions of the 13 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 13 amino acids, of which at least 69.2%, preferably at least 76.9%, more preferably at least 84.6%, most preferably at least 92.3% are identical to 13 consecutive amino acids of SEQ ID NO.1 and the position of the 9, respective 10 or 11 or 12 identical amino acids is also identical when compared to the respective positions of the 13 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 13 amino acids, of which 9, preferably 10, more preferably 11, most preferably 12 are identical to 13 consecutive amino acids of column I of table 10.

In a further embodiment [AA] consists of 13 amino acids, of which 9, preferably 10, more preferably 11, most preferably 12, more preferably 13 are identical compared to 13 consecutive amino acids of SEQ ID NO.1. Any possible 13 consecutive amino acids of SEQ ID NO.1 are listed in table 10.

Thus in this embodiment of the invention, [AA] consists of 13 amino acids, of which at least 69.2%, preferably at least 76.9%, more preferably at least 84.6%, most preferably at least 92.3%, most preferably 100% are identical to 13 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 13 amino acids, of which 9 amino acids, preferably 10 amino acids, more preferably 11 amino acids, most preferably 12 amino acids are identical compared to 13 consecutive amino acids of SEQ ID NO.1 and the position of the 9, respective 10 or 11 or 12 identical amino acids is also identical when compared to the respective position of the 13 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of least 13 amino acids, of which 9, preferably 10, more preferably 11, most preferably 12 are identical to 13 consecutive amino acids of column I of table 10.

In a further embodiment [AA] consists of at most 15, preferably at most 14, of which 9, preferably 10, more preferably 11, most preferably 12, most preferably 13 amino acids, are identical to 13 consecutive amino acids of SEQ ID NO.1.

In a further embodiment [AA] consists of at most 15, preferably at most 14, of which 9 amino acids, preferably 10, more preferably 11, most preferably 12 amino acids, are identical to 13 consecutive amino acids of SEQ ID NO.1 and the position of the 9, respective 10 or 11 or 12 amino acids is identical to the positions of respective amino acids of the 13 amino acids of SEQ ID NO.1. In this embodiment of the invention, also the position of the 9, respective 10 or 11 or 12 amino acids is identical when compared to the respective positions of 13 consecutive amino acids of SEQ ID NO.1.

[AA] Moiety: Tetradecapeptides

In a further embodiment [AA] comprises at least 14 amino acids, of which 10, preferably 11, more preferably 12, most preferably 13, most preferably 14 amino acids are identical compared to 14 consecutive amino acids of SEQ ID NO.1. Any possible 14 consecutive amino acids of SEQ ID NO.1 are listed in Table 11.

Thus in this embodiment of the invention, [AA] comprises at least 14 amino acids, of which at least 71.4%, preferably at least 78.6%, more preferably at least 85.7%, most preferably at least 92.9%, most preferably 100% are identical to 14 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 14 amino acids, of which 10 amino acids, preferably 11 amino acids, more preferably 12, most preferably 13 amino acids are identical compared to 14 consecutive amino acids of SEQ ID NO.1 and the position of the 10, respective 11, 12 or 13 identical amino acids is also identical when compared to the respective positions of the 14 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 14 amino acids, of which at least 71.4%, preferably at least 78.6%, more preferably at least 85.7%, most preferably at least 92.9% are identical to 14 consecutive amino acids of SEQ ID NO.1 and the position of the 10, respective 11, 12 or 13 identical amino acids is also identical when compared to the respective positions of the 14 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 14 amino acids, of which 10, preferably 11, more preferably 12, most preferably 13 are identical to 14 consecutive amino acids of column I of table 11.

In a further embodiment [AA] consists of 14 amino acids, of which 10, preferably 11, more preferably 12, most preferably 13, most preferably 14 are identical compared to 14 consecutive amino acids of SEQ ID NO.1. Any possible 14 consecutive amino acids of SEQ ID NO.1 are listed in table 11.

Thus in this embodiment of the invention, [AA] consists of 14 amino acids, of which at least 71.4%, preferably at least 78.6%, more preferably at least 85.7%, most preferably at least 92.9%, most preferably 100% are identical to 14 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 14 amino acids, of which 10 amino acids, preferably 11 amino acids, more preferably 12 amino acids, most preferably 13 amino acids are identical compared to 14 consecutive amino acids of SEQ ID NO.1 and the position of the 10, respective 11 or 12 or 13 identical amino acids is also identical when compared to the respective position of the 14 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 14 amino acids, of which 10, preferably 11, more preferably 12, most preferably 13 are identical to 14 consecutive amino acids of column I of table 11.

In a further embodiment [AA] consists of at most 15, preferably at most 14, of which 10 amino acids, preferably 11, more preferably 12, most preferably 13, most preferably 14 amino acids, are identical to 14 consecutive amino acids of SEQ ID NO. 1.

In a further embodiment [AA] consists of at most 15, preferably at most 14, of which 10 amino acids, preferably 11, more preferably 12, most preferably 13 amino acids, are identical to 14 consecutive amino acids of SEQ ID NO.1 and the position of the 10, respective 11, 12 or 13 amino acids is identical to the positions of respective amino acids of the 14 amino acids of SEQ ID NO.1. In this embodiment of the invention, also the position of the 10, respective 11 or 12 or 13 amino acids is identical when compared to the respective positions of 14 consecutive amino acids of SEQ ID NO.1.

[AA] Moiety: Pentadecapeptides

In a further embodiment [AA] consists of 15 amino acids, of which 10, preferably 11, more preferably 12, most preferably 13, most preferably 14, most preferably 15 amino acids are identical compared to 15 consecutive amino acids of SEQ ID NO.1.

Any possible 15 consecutive amino acids of SEQ ID NO.1 are listed in Table 12. Thus in this embodiment of the invention, [AA] consists of 15 amino acids, of which at least 66.6%, preferably at least 73.3%, more preferably at least 80%, most preferably at least 86.7%, most preferably at least 93.3%, most preferably 100% are identical to 15 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 15 amino acids, of which 10 amino acids, preferably 11 amino acids, more preferably 12, most preferably 13, most preferably 14 amino acids are identical compared to 15 consecutive amino acids of SEQ ID NO.1 and the position of the 10, respective 11, 12, 13 or 14 identical amino acids is also identical when compared to the respective positions of the 15 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] consists of 15 amino acids, of which at least 66.6%, preferably at least 73.3%, more preferably at least 80%, most preferably at least 86.7%, most preferably at least 93.3% are identical to 15 consecutive amino acids of SEQ ID NO.1 and the position of the 10, respective 11, 12, 13 or 14 identical amino acids is also identical when compared to the respective positions of the 15 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 15 amino acids, of which 10, preferably 11, more preferably 12, most preferably 13, most preferably 14, most preferable 15 are identical to 15 consecutive amino acids of column I of table 12.

[AA] Moiety Pentapeptides

In a preferred embodiment [AA] comprises at least 5 amino acids, of which 4 amino acids, preferably 5 amino acids are identical compared to 5 consecutive amino acids of SEQ ID NO.1 and the position of the 4, respective 5 identical amino acids is also identical when compared to the respective positions of the 5 amino acids of SEQ ID NO.1. Any possible 5 consecutive amino acids of SEQ ID NO.1 are listed in Table 2.

Thus in this embodiment of the invention [AA] comprises at least 5 amino acids, of which at least 70%, preferably 100% are identical to 5 consecutive amino acids of SEQ ID NO.1 and the position of the 4, respective 5 identical amino acids is also identical when compared to the respective positions of the 5 amino acids of SEQ ID NO.1, preferably when compared to 5 consecutive amino acids of column I of table 2.

In a preferred embodiment [AA] consists of 5 amino acids, of which 4 amino acids, preferably 5 amino acids are identical compared to 5 consecutive amino acids of SEQ ID NO.1 and the position of the 4, respective 5 identical amino acids is also identical when compared to the respective position of the 6 amino acids of SEQ ID NO.1, preferably when compared to 5 consecutive amino acids of column I of table 2.

In a further embodiment [AA] consists of at most 15, preferably at most 10, more preferably at most 8 amino acids, of which 4 amino acids, preferably 5 amino acids, are identical to 5 consecutive amino acids of SEQ ID NO.1 and the position of the 4, respective 5 identical amino acids is also identical when compared to the respective positions of the 5 amino acids of SEQ ID NO.1, preferably when compared to 5 consecutive amino acids of column I of table 2.

In a further embodiment [AA] consists of at most 15, preferably at most 10, more preferably at most 8 amino acids, of which 4 amino acids, preferably 5 amino acids, are identical to 5 consecutive amino acids of SEQ ID NO.1 and the position of the 4, respective 5 amino acids is identical to the positions of respective amino acids of the 5 amino acids of SEQ ID NO. 1, preferably when compared to 5 consecutive amino acids of column I of table 2.

R1 Moiety

The amino-terminal part of [AA] is linked via R1. R1 is chosen from the group consisting of

-   -   a) —H     -   b) is a linear saturated or unsaturated or branched saturated or         unsaturated acyl group having 1 to 24 carbon atoms, which may be         functionalised by a —OH, SH, —COOH or —CONH₂ group, or     -   c) a sterol or a sphingolipid group which is joined to the amino         terminal part of [AA] via a bifunctional linker.

In embodiment a) the amino terminal is not substituted but consists of an amino group. It is within the scope of the invention that, in case R1=H, the oligopeptide of the invention can be protonated, and be present as salt, e.g. as chloride, bromide, fluoride or iodide.

In a preferred embodiment of the invention R1 is a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24 carbon atoms, preferably 1 to 6, preferably 1 to 12, preferably 10 to 20, more preferably 12 to 18 carbon atoms.

The radical R1 is preferably chosen from the group which is formed by acetyl (CH₃CO—), ethanoyl (CH₃—CH₂—CO—), propionyl, butanoyl (=butyryl; CH₃—(CH₂)₂—CO—), decanoyl, palmitoyl (CH₃—(CH₂)₁₄—CO—), stearoyl (CH₃—(CH₂)₁₆—CO—), oleyl, lipoyl, linoleyl or conjugated linoleyl, particularly preferable the group is acetyl.

In one embodiment of the invention the acyl group can be further functionalised by one or more of the functional groups selected from the group consisting of —OH, —SH, —COOH and —CONH₂.

In one embodiment of the invention R1 is a sterol group. The sterol group can be selected from plant sterol or from sterol of animal origin.

Sterols in the context of the invention are steroids which only contain a hydroxyl group but no other functional groups at C-3. Formally, therefore, they are alcohols which is why this group of compounds is also referred to occasionally as sterols. In general, sterols contain from about 27 to about 30 carbon atoms and one double bond in the 5/6 position and occasionally in the 7/8, 8/9 or other positions. Sterols which may be used for the purposes of the invention are those obtained from natural products such as, for example, soya, rapeseed, sunflower, coconut, palm kernel and palm oil. Preferred sterols are sigmasterol, campesterol, sitosterol, brassicasterots, stigmasterol, D5 avenasterol, D7 avenasterol, ergosterol, citrostadienol, cholesterol, lanosterols, spongosterols, fungisterols, stellasterols, zymosterols and mixtures thereof and, more particularly, phytosterols based on ergosterols, avenasterols (D5 and D7 avenasterol), campesterols, stigmasterols, sitosterols, brassicasterols, citrosdandiols, sigmastandiols and mixtures thereof. Any other phytosterols known to the expert may also be used.

In a preferred embodiment the sterol group is selected from the group consisting of cholesterol, stigmasterol, sitosterol, or brassicasterol.

In one embodiment R1 is a sphingolipid, preferably sphingolipids are selected from the group consisting of sphingosine, phytosphingosine, dehydrosphingosine or deshuydrophytosphingosine.

The sterol or the sphingolipide are linked to the oligopeptides using a bifunctional linker such as a diacid, for example succinic acid. The sterol hydroxyl group at C-3 can be linked via an ester bond to the bifunctional linker, with can be linked via an amide bond to the amino-terminal part of [AA]. The sphingolipid amino group at C-1 can be linked via an amide bond to the bifunctional linker, which can be linked via an amide bond to the amino-terminal part of [AA].

R2 Moiety

The carboxy terminal part of [AA] is linked via the 0=0 group of the carboxy terminal amino acids of [AA] and is chosen from the group which consists of

-   -   a) —OH     -   b) —NH₂     -   c) a linear saturated or unsaturated or branched saturated or         unsaturated alkoxy group having 1 to 24 carbon atoms, which may         be functionalised by a —OH, —SH, —COOH or —CONH₂ group, or     -   d) a sterol or a sphingolipid group.

In embodiment a) the carboxy terminal is not substituted but consists of a free carboxy group. It is within the scope of the invention that, in case R2=OH, the carboxygroup of the oligopeptide of the invention can be deprotonated, and be present as salt, e.g. as potassium or sodium salt.

In embodiment b) the carboxy terminal is linked to an amino group. It is within the scope of the invention, that, in case R2=NH₂, the NH₂ group of can be protonated, and be present as a salt, e.g. as chloride, bromide, fluoride or iodide.

In a preferred embodiment of the invention R2 is a linear saturated or unsaturated or branched saturated or unsaturated alkoxy group having 1 to 24 carbon atoms, preferably 1 to 6, preferably 10 to 20, more preferably 12 to 18 carbon atoms.

In one embodiment of the invention the alkoxy group can be further functionalised by one or more of the functional groups selected from the group consisting of —OH, —SH, —COOH and —CONH₂.

In one embodiment of the invention R2 is a sterol. Suitable sterols are described under “R1 moieties”. The sterol is linked to the C═O group of the carboxy terminus of [AA] via the 3-hydroxy group, thus resulting in an ester.

In one embodiment of the invention R1 is a sphingolipid. Suitable sphingolipids are described under “R2 moieties”. The sphingolipid is linked to via its amino group to the terminal 0=0 group of the carboxy terminus of [AA], resulting in an amide.

Preferred Oligopeptides

Preferred oligopeptides according to the invention are oligopeptides with the structure of formula (I) wherein R1=a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl), which may be functionalised by a —OH, —SH, —COOH or —CONH₂ group.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a tetra peptide as specified in table 1, preferably column I of table 1 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Especially preferred are oligopeptides of formula (I), wherein [AA] consist of a tetrapeptide selected from the group consisting of

-   -   i) Arg Arg Arg Pro (SEQ ID NO. 2); Arg Arg Pro Arg (SEQ ID NO.         3);     -   ii) Arg Pro Pro Tyr (SEQ ID NO. 6); Pro Pro Tyr Leu (SEQ ID NO.         7); preferably Pro Pro Tyr Leu (SEQ ID NO.7);     -   iii) Pro Tyr Leu Pro (Seq. ID NO. 8); Tyr Leu Pro Arg (SEQ ID         NO. 9); or     -   iv) Tyr Leu Pro Arg (Seq. ID NO. 9); Leu Pro Arg Pro (SEQ ID NO.         10);         and R1 is selected from a linear saturated or unsaturated or         branched saturated or unsaturated acyl group having 1 to 12         carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a tetra peptide as specified in table 1, preferably column I of table 1 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Especially preferred are oligopeptides of formula (I), wherein [AA] consist of a tetrapeptide selected from the group consisting of

-   -   i) Arg Arg Arg Pro (SEQ ID NO.2); Arg Arg Pro Arg (SEQ ID NO.3);     -   ii) Arg Pro Pro Tyr (SEQ ID NO.6); Pro Pro Tyr Leu (SEQ ID         NO.7); preferably Pro Pro Tyr Leu (SEQ ID NO.7);     -   iii) Pro Tyr Leu Pro (Seq. ID NO. 8); Tyr Leu Pro Arg (SEQ ID         NO. 9); or     -   iv) Tyr Leu Pro Arg (SEQ ID NO. 9); Leu Pro Arg Pro (SEQ ID NO.         10);         and wherein R1=acetyl and R2=OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a penta peptide as specified in table 2, preferably column I of table 2 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] is selected from the group consisting of Arg Arg Arg Pro Arg (SEQ ID NO. 38); Arg Pro Pro Tyr Leu (SEQ ID NO. 42); Pro Tyr Leu Pro Arg (SEQ ID NO. 44); or Tyr Leu Pro Arg Pro (SEQ ID NO. 45); and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a penta peptide as specified in table 2, preferably column I of table 2 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] is selected from the group consisting of Arg Arg Arg Pro Arg (SEQ ID NO. 38); Arg Pro Pro Tyr Leu (SEQ ID NO. 42); Pro Tyr Leu Pro Arg (SEQ ID NO. 44); and Tyr Leu Pro Arg Pro (SEQ ID NO. 45); and wherein R1=acetyl and R2=OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a hexa peptide as specified in table 3, preferably column I of table 3 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a hexa peptide as specified in table 3, preferably column I of table 3 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a hepta peptide as specified in table 4, preferably column I of table 4 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a hepta peptide as specified in table 4, preferably column I of table 4 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of an octa peptide as specified in table 5, preferably column I of table 5 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of an acta peptide as specified in table 5, preferably column I of table 5 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a nona peptide as specified in table 6, preferably column I of table 6 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a nona peptide as specified in table 6, preferably column I of table 6 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a deca peptide as specified in table 7, preferably column I of table 7 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a deca peptide as specified in table 7, preferably column I of table 7 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of an undeca peptide as specified in table 8, preferably column I of table 8 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of an undeca peptide as specified in table 8, preferably column I of table 8 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of an dodeca peptide as specified in table 9, preferably column I of table 9 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of an dodeca peptide as specified in table 9, preferably column I of table 9 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a trideca peptide as specified in table 10, preferably column I of table 10 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a trideca peptide as specified in table 10, preferably column I of table 10 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a tetradeca peptide as specified in table 11, preferably column I of table 11 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a tetradeca peptide as specified in table 11, preferably column I of table 11 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a pentadeca peptide as specified in table 12, preferably column I of table 11 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl).

Preferred according to the invention are oligopeptides of formula (I), wherein [AA] consists of a pentadeca peptide as specified in table 12, preferably column I of table 12 and R1 is selected from a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24, preferably 1 to 12 carbon atoms, preferably 1 to 6, most preferably 2 (=acetyl) and R2=—OH.

In a preferred embodiment of the invention n is at least 4, preferably at least 5; [AA] is selected from the amino acids no. 1 to 15 of SEQ ID NO.1, preferably from the amino acids no. 1-5, preferably from the amino acids 5-9, more preferably from the amino acids 6-9, preferably from the amino acids 7-11, more preferably from the amino acids 8-12 of SEQ ID NO.1.

Oligopeptides of Formula (II)

One embodiment of the invention is directed to the cosmetic use of oligopeptides of structure (II) for stimulating the renewal rate of skin and/or hair. They are preferably useful cosmetic preparations against the reduction in cell numbers in human skin or for stimulating and/or regenerating hair growth and against hair loss.

In one embodiment, the oligopeptide according to the formula (II) are especially useful for the cosmetic treatment of

-   -   l. human skin or hair ageing and/or     -   m. for preventing against ageing symptoms, such as wrinkles,         and/or     -   n. decrease of the epidermal and dermal skin layers, and/or     -   o. alterations of the extracellular matrix and/or decrease in         the renewal of epidermal and dermal cells and/or     -   p. modifications of the dermal epidermal junctions and/or     -   q. loss of elasticity and/or     -   r. hair damages and/or hair losses.

In one embodiment, the oligopeptides are preferably useful for

-   -   s. stimulation of the renewal rate of human skin and/or hair.

In a preferred embodiment, the oligopeptides are used for

-   -   t. producing cosmetic preparations which are effective for         stimulating the production of mRNA and/or     -   u. for stimulation of matrix proteins such as collagen, elastin         or proteoglycans and/or     -   v. for stimulation of syndecan-1 synthesis

Oligopeptides of formula (II):

R1-[AA]_(n)-R2  (II)

wherein [AA] comprises at least 4 amino acids of which at least 3, are identical compared to 4 consecutive amino acids of SEQ ID NO. 1 and/or wherein [AA] comprises at least 5 amino acids of which at least 4 are identical to 5 consecutive amino acids of SEQ ID NO. 1 wherein n=4 to 15 wherein R1 is linked to the NH₂-group of the amino-terminal part of [AA] and is chosen from the group which is formed from

-   -   a) —H     -   b) a linear saturated or unsaturated or branched saturated or         unsaturated acyl group having 1 to 24 carbon atoms, which may be         functionalized by a —OH, —SH, —COOH or —CONH₂ group,     -   c) a sterol or a sphingolipid group which is joined to the amino         terminal part of [AA] via a bifunctional linker         wherein R2 is linked to the C═O group of the carboxy-terminal         part of [AA] and is chosen from the group which is formed from     -   a) —OH,     -   b) —NH₂     -   c) a linear saturated or unsaturated or branched saturated or         unsaturated alkoxy group having 1 to 24 carbon atoms     -   d) or a sterol or a sphingolipid group.

In this embodiment [AA] comprises at least 4 amino acids, of which at least 3 are identical compared to 4 consecutive amino acids of SEQ ID NO.1. Any possible 4 consecutive amino acids of SEQ ID NO.1 are listed in Table 1.

Thus in this embodiment of the invention, [AA] comprises at least 4 amino acids, of which at least 75%, preferably 100% are identical to 4 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 4 amino acids, of which at least 3 amino acids are identical compared to 4 consecutive amino acids of SEQ ID NO. 1 and the position of the 3 identical amino acids is also identical when compared to the respective positions of the 4 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 4 amino acids, of which at least 75%, are identical to 4 consecutive amino acids of SEQ ID NO.1 and the position of the 3 identical amino acids is also identical when compared to the respective positions of the 4 amino acids of SEQ ID NO.1.

In following chart illustrates this embodiment of the invention. X and Yare further amino acids.

Position No. 1 2 3 4 SEQ 10 No. 1 Arg Arg Arg Pro [AA] Arg X Arg Pro [AA] Arg Arg Arg Y

In a preferred embodiment [AA] comprises at least 4 amino acids, of which at least 3, are identical to 4 consecutive amino acids of column I of table 1.

In a further embodiment [AA] consists of 4 amino acids, of which at least 3 are identical compared to 4 consecutive amino acids of SEQ ID NO.1. Any possible 4 consecutive amino acids of SEQ ID NO.1 are listed in Table 1.

Thus in this embodiment of the invention, [AA] consists of 4 amino acids, of which at least 75%, preferably 100% are identical to 4 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 4 amino acids, of which at least 3 amino acids, are identical compared to 4 consecutive amino acids of SEQ ID NO.1 and the position of the 3 identical amino acids is also identical when compared to the respective position of the 4 amino acids of SEQ ID NO.1.

In this embodiment [AA] comprises at least 5 amino acids, of which at least 4 are identical compared to 5 consecutive amino acids of SEQ ID NO.1. Any possible 5 consecutive amino acids of SEQ ID NO.1 are listed in Table 2.

Thus in this embodiment of the invention, [AA] comprises at least 5 amino acids, of which at least 80%, preferably 100% are identical to 4 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 5 amino acids, of which at least 4 amino acids are identical compared to 5 consecutive amino acids of SEQ ID NO.1 and the position of the 4 identical amino acids is also identical when compared to the respective positions of the 5 amino acids of SEQ ID NO.1.

Thus in this embodiment of the invention [AA] comprises at least 5 amino acids, of which at least 80%, are identical to 5 consecutive amino acids of SEQ ID NO.1 and the position of the 4 identical amino acids is also identical when compared to the respective positions of the 5 amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] comprises at least 5 amino acids, of which at least 4, are identical to 5 consecutive amino acids of column I of table 1.

In a further embodiment [AA] consists of 5 amino acids, of which at least 4 are identical compared to 5 consecutive amino acids of SEQ ID NO.1. Any possible 5 consecutive amino acids of SEQ ID NO.1 are listed in Table 2.

Thus in this embodiment of the invention, [AA] consists of 5 amino acids, of which at least 80%, preferably 100% are identical to 5 consecutive amino acids of SEQ ID NO.1.

In a preferred embodiment [AA] consists of 5 amino acids, of which at least 4 amino acids, are identical compared to 5 consecutive amino acids of SEQ ID NO.1 and the position of the 4 identical amino acids is also identical when compared to the respective position of the 5 amino acids of SEQ ID NO.1.

Oligopeptides

A further embodiment of the invention relates to oligopeptides of formula (II)

R1-[AA]_(n)-R2  (II)

wherein [AA] comprises at least 4 amino acids of which at least 3, are identical compared to 4 consecutive amino acids of SEQ ID NO. 1 and/or wherein [AA] comprises at least 5 amino acids of which at least 4 are identical to 5 consecutive amino acids of SEQ ID NO.1 wherein n=4 to 15, preferably n=4, n=5. wherein R1 is linked to the NH₂ group of the amino-terminal part of [AA] and is chosen from the group which is formed from

-   -   a) —H,     -   b) a linear saturated or unsaturated or branched saturated or         unsaturated acyl group having 1 to 24 carbon atoms, which may be         functionalized by a —OH, —SH, —COOH or —CONH₂ group,     -   c) a sterol or a sphingolipid group which is joined to the amino         terminal part of [AA] via a bifunctional linker         wherein R2 is linked to the C═O group of the carboxy-terminal         part of [AA] and is chosen from the group which is formed from     -   a) —OH,     -   b) —NH₂     -   c) a linear saturated or unsaturated or branched saturated or         unsaturated alkoxy group having 1 to 24 carbon atoms     -   d) or a sterol or a sphingolipid group         with the proviso that if R1 is —H, R2 is not —OH; or that if R2         is —OH, R1 is not —H; and         with the proviso that [AA] is not Arg Lys Pro Arg (SEQ ID NO.         367), Phe-Tyr-Arg-Pro-Arg (SEQ ID NO. 372), Ala-Arg-Asp-Pro-Arg         (SEQ ID NO. 373).

Surprisingly it has been found that these oligopeptides can be used in cosmetic compositions, preferably for stimulating the renewal rate of skin and/or hair.

Synthesis of Oligopeptides

The oligogpeptides according to the invention can be obtained by chemical or enzymatic synthesis or by controlled hydrolysis of natural proteins of microorganisms, plants or animals which contain the sequence as in SEQ ID NO.1. The hydrolysate comprising the sequence as in SEQ ID NO.1 or at least one fragment of at least four amino acids of SEQ ID NO.1 or the position 1-15 or 1-5, or 5-9, or 6-9, or 7-11, or 8-12 of SEQ ID NO.1 obtained by hydrolysis of natural proteins can be purified by known techniques such as membrane filtration, chromatography or immunoprecipitation. The oligopeptides can also be produced by microorganisms, which either naturally form the oligopeptides, or have possibly been genetically modified or are manipulated in some other way during fermentation through fermentation conditions such that they form the oligopeptides according to the invention. The amino acids can either occur in the L, the D, or the DL form in the peptide fragment.

Cosmetic Compositions

One embodiment of the invention is directed to cosmetic compositions comprising at least one oligopeptide of the structure of formula (I).

The oligopeptide are preferably used in a concentration from 0.05 to 500 ppm, preferably from 0.5 to 100 ppm.

The oligopeptides are preferably dissolved in one or more solvents which are approved for cosmetic preparations, such as, for example, water, glycerin, propylene glycol, butylene glycol, ethoxylated or propoxylated diglycols, ethanol, propanol, isopropanol or mixtures of said solvents. Furthermore, it is possible to use the oligopeptides solubilized in liposomes or adsorbed to organic polymers or similar material which is acceptable for topical application. Besides the solvents, further auxiliaries and additives may also be present in the preparations which are used according to the invention.

Cosmetic and/or Dermatological Preparations

The oligopeptides and the cosmetic uses according to the invention can serve for producing cosmetic preparations, such as, for example, hair shampoos, hair lotions, foam baths, shower baths, creams, gels, lotions, alcoholic and aqueous/alcoholic solutions, emulsions, wax/fat masses, stick preparations, powders or ointments. These preparations can also comprise, as further auxiliaries and additives, mild surfactants, oil bodies, emulsifiers, pearlescent waxes, consistency regulators, thickeners, superfatting agents, stabilizers, polymers, silicone compounds, fats, waxes, lecithins, phospholipids, UV photoprotective factors, biogenic active ingredients, antioxidants, deodorants, antiperspirants, antidandruff agents, film formers, swelling agents, insect repellents, self-tanning agents, tyrosine inhibitors (depigmentation agents), hydrotropes, solubilizers, preservatives, perfume oils, dyes and the like.

Surfactants

Surface-active substances which may be present are anionic, nonionic, cationic and/or amphoteric or zwitterionic surfactants, the content of which in the compositions is usually about 1 to 70% by weight, preferably 5 to 50% by weight and in particular 10 to 30% by weight. Typical examples of anionic surfactants are soaps, alkylbenzenesulphonates, alkanesulphonates, olefinsulphonates, alkyl ether sulphonates, glycerol ether sulphonates, a-methyl ester sulphonates, sulpho fatty acids, alkyl sulphates, alkyl ether sulphates, glycerol ether sulphates, fatty acid ether sulphates, hydroxy mixed ether sulphates, monoglyceride (ether) sulphates, fatty acid amide (ether) sulphates, mono- and dialkyl sulphosuccinates, mono- and dialkyl sulphosuccinamates, sulphotriglycerides, amide soaps, ether carboxylic acids and salts thereof, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, Nacylaminoacids, such as, for example, acyl lactylates, acyl tartrates, acyl glutamates and acyl aspartates, alkyl oligoglucoside sulphates, protein fatty acid condensates (in particular wheat-based vegetable products) and alkyl (ether) phosphates. If the anionic surfactants comprise polyglycol ether chains, these can have a conventional homologue distribution, but preferably have a narrowed homologue distribution. Typical examples of nonionic surfactants are fatty alcohol polyglycol ethers, alkylphenol polyglycol ethers, fatty acid polyglycol esters, fatty acid amide polyglycol ethers, fatty amine polyglycol ethers, alkoxylated triglycerides, mixed ethers and mixed formals, optionally partially oxidized alk(en)yl oligoglycosides and glucoronic acid derivatives, fatty acid N-alkylglucamides, protein hydrolysates (in particular wheat-based vegetable products), polyol fatty acid esters, sugar esters, sorbitan esters, polysorbates and amine oxides. If the nonionic surfactants contain polyglycol ether chains, these can have a conventional homologue distribution, but preferably have a narrowed homologue distribution. Typical examples of cationic surfactants are quaternary ammonium compounds, such as, for example, dimethyldistearylammonium chloride, and ester quats, in particular quaternized fatty acid trialkanolamine ester salts. Typical examples of amphoteric and zwitterionic surfactants are alkylbetaines, alkylamidobetaines, aminopropionates, aminoglycinates, imidazoliniumbetaines and sulphobetaines. The specified surfactants are exclusively known compounds. Typical examples of particularly suitable mild, i.e. particularly skin-compatible, surfactants are fatty alcohol polyglycol ether sulphates, monoglyceride sulphates, mono- and/or dialkyl sulphosuccinates, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates, u-olefinsulphonates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucamides, alkylamidobetaines, amphoacetals and/or protein fatty acid condensates, the latter preferably being based on wheat proteins.

Oil Bodies

Suitable oil bodies are, for example, Guerbet alcohols based on fatty alcohols having 6 to 18, preferably 8 to 10, carbon atoms, esters of linear C₆-C₂₂-fatty acids with linear or branched C₆-C₂₂ fatty alcohols and/or esters of branched C₆-C₁₃ carboxylic acids with linear or branched C₆-C₂₂ fatty alcohols, such as, for example, myristyl myristate, myristyl palmitate, myristyl stearate, myristyl isostearate, myristyl oleate, myristyl behenate, myristyl erucate, cetyl myristate, cetyl palmitate, cetyl stearate, cetyl isostearate, cetyl oleate, cetyl behenate, cetyl erucate, stearyl myristate, stearyl palmitate, stearyl stearate, stearyl isostearate, stearyl oleate, stearyl behenate, stearyl erucate, isostearyl myristate, isostearyl palmitate, isostearyl stearate, isostearyl isostearate, isostearyl oleate, isostearyl behenate, isostearyl oleate, oleyl myristate, oleyl palmitate, oleyl stearate, oleyl isostearate, oleyl oleate, oleyl behenate, oleyl erucate, behenyl myristate, behenyl palmitate, behenyl stearate, behenyl isostearate, behenyl oleate, behenyl behenate, behenyl erucate, erucyl myristate, erucyl palmitate, erucyl stearate, erucyl isostearate, erucyl oleate, erucyl behenate and erucyl erucate. Also suitable are esters of linear C₆C₂₂-fatty acids with branched alcohols, in particular 2-ethylhexanol, esters of C₁₈-C₃₈-alkyl hydroxycarboxylic acids with linear or branched C₆-C₂₂ fatty alcohols (cf. DE 19756377 A1), in particular dioctyl malates, esters of linear and/or branched fatty acids with polyhydric alcohols (such as, for example, propylene glycol, dimerdiol or trimertriol) and/or Guerbet alcohols, triglycerides based on C₆-C₁₀-fatty acids, liquid mono-/di-/triglyceride mixtures based on C₆-C₁₈-fatty acids, esters of C₆-C₂₂-fatty alcohols and/or Guerbet alcohols with aromatic carboxylic acids, in particular benzoic acid, esters of C₂-C₁₂-dicarboxylic acids with linear or branched alcohols having 1 to 22 carbon atoms or polyols having 2 to 10 carbon atoms and 2 to 6 hydroxyl groups, vegetable oils, branched primary alcohols, substituted cyclohexanes, linear and branched C₆-C₂₂-fatty alcohol carbonates, such as, for example, dicaprylyl carbonate (Cetiol® CC), Guerbet carbonates based on fatty alcohols having 6 to 18, preferably 8 to 10, carbon atoms, esters of benzoic acid with linear and/or branched C₆-C₂₂ alcohols (e.g. Fins® Iv® TN), linear or branched, symmetrical or unsymmetrical dialkyl ethers having 6 to 22 carbon atoms per alkyl group, such as, for example, dicaprylyl ether (Cetiol® OE), ring-opening products of epoxidized fatty acid esters with polyols, silicone oils (cyclomethicones, silicon methicone types, inter alia) and/or aliphatic or naphthenic hydrocarbons, such as, for example, squalane, squalene or dialkylcyclohexanes.

Emulsifiers

Suitable emulsifiers are, for example, nonionogenic surfactants from at least one of the following groups:

-   -   addition products of from 2 to 30 mol of ethylene oxide and/or a         to 5 mol of propylene oxide to linear fatty alcohols having 8 to         22 carbon atoms, to fatty acids having 12 to 22 carbon atoms, to         alkylphenols having 8 to 15 carbon atoms in the alkyl group, and         alkylamines having 8 to 22 carbon atoms in the alkyl radical;     -   alkyl and/or alkenyl oligoglycosides having 8 to 22 carbon atoms         in the alk(en)yl radical and the ethoxylated analogues thereof;     -   addition products of from 1 to 15 mol of ethylene oxide to         castor oil and/or hydrogenated castor oil;     -   addition products of from 15 to 60 mol of ethylene oxide to         castor oil and/or hydrogenated castor oil;     -   partial esters of glycerol and/or sorbitan with unsaturated,         linear or saturated, branched fatty acids having 12 to 22 carbon         atoms and/or hydroxycarboxylic acids having 3 to 18 carbon         atoms, and the adducts thereof with 1 to 30 mol of ethylene         oxide;     -   partial esters of polyglycerol (average degree of         self-condensation 2 to 8), polyethylene glycol (molecular weight         400 to 5 000), trimethylolpropane, pentaerythritol, sugar         alcohols (e.g. sorbitol), alkyl glucosides (e.g. methyl         glucoside, butyl glucoside, lauryl glucoside), and         polyglucosides (e.g. cellulose) with saturated and/or         unsaturated, linear or branched fatty acids having 12 to 22         carbon atoms and/or hydroxycarboxylic acids having 3 to 18         carbon atoms, and the adducts thereof with 1 to 30 mol of         ethylene oxide;     -   mixed esters of pentaerythritol, fatty acids, citric acid and         fatty alcohol and/or mixed esters of fatty acids having 6 to 22         carbon atoms, methylglucose and polyols, preferably glycerol or         polyglycerol,     -   mono-, di- and trialkyl phosphates, and mono-, di- and/or         tri-PEG alkyl phosphates and salts thereof;     -   wool wax alcohols;     -   polysiloxane-polyalkyl-polyether copolymers and corresponding         derivatives;     -   block copolymers, e.g. polyethylene glycol-30         dipolyhydroxystearates;     -   polymer emulsifiers, e.g. Pemulen grades (TR-1, TR-2) from         Goodrich;     -   polyalkylene glycols, and     -   glycerol carbonate.

Ethylene Oxide Addition Products

The addition products of ethylene oxide and/or of propylene oxide to fatty alcohols, fatty acids, alkylphenols or to castor oil are known, commercially available products. These are homologue mixtures whose average degree of alkoxylation corresponds to the ratio of the amounts of substance of ethylene oxide and/or propylene oxide and substrate with which the addition reaction is carried out. C12118-fatty acid mono- and diesters of addition products of ethylene oxide to glycerol are known as refatting agents for cosmetic preparations.

Alkyl and/or Alkenyl Oligoglycosides

Alkyl and/or alkenyl oligoglycosides, their preparation and their use are known from the prior art. They are prepared, in particular, by reacting glucose or oligosaccharides with primary alcohols having 8 to 18 carbon atoms. With regard to the glycoside radical, both monoglycosides, in which a cyclic sugar radical is glycosidically bonded to the fatty alcohol, and also oligomeric glycosides having a degree of oligomerization of up to, preferably, about 8, are suitable. The degree of oligomerization here is a statistical average value which is based on a homologue distribution customary for such technical-grade products.

Partial Glycerides

Typical examples of suitable partial glycerides are hydroxystearic acid monoglyceride, hydroxystearic acid diglyceride, isostearic acid monoglyceride, isostearic acid diglyceride, oleic acid monoglyceride, oleic acid diglyceride, ricinoleic acid monoglyceride, ricinoleic acid diglyceride, linoleic acid monoglyceride, linoleic acid diglyceride, linolenic acid monoglyceride, linolenic acid diglyceride, erucic acid monoglyceride, erucic acid diglyceride, tartaric acid monoglyceride, tartaric acid diglyceride, citric acid monoglyceride, citric acid diglyceride, malic acid monoglyceride, malic acid diglyceride, and the technicalgrade mixtures thereof which may also comprise small amounts of triglyceride as a minor product of the preparation process. Likewise suitable are addition products of 1 to 30 mol, preferably 5 to 10 mol, of ethylene oxide to said partial glycerides.

Sorbitan Esters

Suitable sorbitan esters are sorbitan monoisostearate, sorbitan sesquiisostearate, sorbitan diisostearate, sorbitan triisostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan dioleate, sorbitan trioleate, sorbitan monoerucate, sorbitan sesquierucate, sorbitan dierucate, sorbitan trierucate, sorbitan monoricinoleate, sorbitan sesquiricinoleate, sorbitan diricinoleate, sorbitan triricinoleate, sorbitan monohydroxystearate, sorbitan sesquihydroxystearate, sorbitan dihydroxystearate, sorbitan trihydroxystearate, sorbitan monotartrate, sorbitan sesquitartrate, sorbitan ditartrate, sorbitan tritartrate, sorbitan monocitrate, sorbitan sesquicitrate, sorbitan dicitrate, sorbitan tricitrate, sorbitan monomaleate, sorbitan sesquimaleate, sorbitan dimaleate, sorbitan trimaleate, and technicalgrade mixtures thereof. Likewise suitable are addition products of from 1 to 30 mol, preferably 5 to 10 mol, of ethylene oxide to said sorbitan esters.

Polyglycerol Esters

Typical examples of suitable polyglycerol esters are polyglyceryl-2 dipolyhydroxystearate (Dehymuls® PGPH), polyglycerol-3 diisostearate (Lameform® TGI), polyglyceryl-4 isostearate (Isolan® GI 34), polyglyceryl-3 oleate, diisostearoyl polyglyceryl-3 diisostearate (Isolan® PDI), polyglyceryl-3 methylglucose distearate (Tego Care® 450), polyglyceryl-3 beeswax (Cera Bellina®), polyglyceryl-4 caprate (Polyglycerol Caprate T201 0/90), polyglyceryl-3 cetyl ether (Chimexane® NL), polyglyceryl-3 distearate (Cremophor® GS 32) and polyglyceryl polyricinoleate (Admul® WOL 1403), polyglyceryl dimerate isostearate, and mixtures thereof. Examples of further suitable polyol esters are the mono-, di- and triesters, optionally reacted with 1 to 30 mol of ethylene oxide, of trimethylolpropane or pentaerythritol with lauric acid, coconut fatty acid, tallow fatty acid, palmitic acid, stearic acid, oleic acid, behenic acid and the like.

Anionic Emulsifiers

Typical anionic emulsifiers are aliphatic fatty acids having 12 to 22 carbon atoms, such as, for example, palmitic acid, stearic acid or behenic acid, and dicarboxylic acids having 12 to 22 carbon atoms, such as, for example, azelaic acid or sebacic acid.

Amphoteric and Cationic Emulsifiers

Furthermore, zwitterionic surfactants can be used as emulsifiers. The term “zwitterionic surfactants” refers to those surface-active compounds which carry at least one quaternary ammonium group and at least one carboxylate and one sulphonate group in the molecule. Particularly suitable zwitterionic surfactants are the so-called betaines, such as N-alkyl-N,N-dimethylammonium glycinates, for example cocoalkyldimethylammonium glycinate, N-acylaminopropyl-N,N-dimethylammonium glycinates, for example cocoacylaminopropyldimethylammonium glycinate, and 2-alkyl-3-carboxymethyl3-hydroxyethylimidazolines having in each case 8 to 18 carbon atoms in the alkyl or acyl group, and cocoacylaminoethylhydroxyethylcarboxymethyl glycinate. Particular preference is given to the fatty acid amide derivative known under the CTFA name Cocamidopropyl Betaine. Likewise suitable emulsifiers are ampholytic surfactants. The term “ampholytic surfactants” means those surfaceactive compounds which, apart from a C8/18-alkyl or -acyl group, contain at least one free amino group and at least one —COOH or —SO₃H group in the molecule and are capable of forming internal salts. Examples of suitable ampholytic surfactants are N-alkylglycines, N-alkylaminopropionic acids, N-alkylaminobutyric acids, N-alkyliminodipropionic acids, N-hydroxyethyl-N-alkylamidopropylglycines, N-alkyltaurines, N-alkylsarcosines, 2-alkylaminopropionic acids and alkylaminoacetic acids having in each case about 8 to 18 carbon atoms in the alkyl group. Particularly preferred ampholytic surfactants are N-cocoalkylaminopropionate, cocoacylaminoethylaminopropionate and C_(12/18)-acylsarcosine. Finally, cationic surfactants are also suitable as emulsifiers, those of the ester quat type, preferably methyl-quaternized difatty acid triethanolamine ester salts, being particularly preferred.

Fats and Waxes

Typical examples of fats are glycerides, i.e. solid or liquid vegetable or animal products which consist essentially of mixed glycerol esters of higher fatty acids, suitable waxes are inter alia natural waxes, such as, for example, candelilla wax, carnauba wax, Japan wax, esparto grass wax, cork wax, guaruma wax, rice germ oil wax, sugarcane wax, ouricury wax, montan wax, beeswax, shellac wax, spermaceti, lanolin (wool wax), uropygial grease, ceresin, ozokerite (earth wax), petrolatum, paraffin waxes, microcrystalline waxes; chemically modified waxes (hard waxes), such as, for example, montan ester waxes, sasol waxes, hydrogenated jojoba waxes, and synthetic waxes, such as, for example, polyalkylene waxes and polyethylene glycol waxes. In addition to the fats, suitable additives are also fat-like substances, such as lecithins and phospholipids. The term lecithins is understood by the person skilled in the art as meaning those glycerophospholipids which are founded from fatty acids, glycerol, phosphoric acid and choline by esterification. Lecithins are thus also often as phosphatidylcholines (PC) in the specialist world. Examples of natural lecithins which may be mentioned are the cephalins, which are also referred to as phosphatidic acids and constitute derivatives of 1,2-diacyl-sn-glycerol-3-phosphoric acids. By contrast, phospholipids are usually understood as meaning mono- and preferably diesters of phosphoric acid with glycerol (glycerol phosphates), which are generally classed as fats. In addition, sphingosines or sphingolipids are also suitable.

Pearlescent Waxes

Examples of suitable pearlescent waxes are: alkylene glycol esters, specifically ethylene glycol distearate; fatty acid alkanolamides, specifically coconut fatty acid diethanolamide; partial glycerides, specifically stearic acid monoglyceride; esters of polybasic, optionally hydroxy-substituted carboxylic acids with fatty alcohols having 6 to 22 carbon atoms, specifically long-chain esters of tartaric acid; fatty substances, such as, for example, fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers and fatty carbonates, which have a total of at least 24 carbon atoms, specifically laurone and distearyl ether; fatty acids, such as stearic acid, hydroxystearic acid or behenic acid, ring-opening products of olefin epoxides having 12 to 22 carbon atoms with fatty alcohols having 12 to 22 carbon atoms and/or polyols having 2 to 15 carbon atoms and 2 to 10 hydroxyl groups, and mixtures thereof.

Consistency Regulators and Thickeners

Suitable consistency regulators are primarily fatty alcohols or hydroxy fatty alcohols having 12 to 22, and preferably 16 to 18, carbon atoms, and also partial glycerides, fatty acids or hydroxy fatty acids. Preference is given to a combination of these substances with alkyl oligoglucosides and/or fatty acid N-methylglucamides of identical chain length and/or polyglycerol poly-12-hydroxystearates. Suitable thickeners are, for example, Aerosil grades (hydrophilic silicas), polysaccharides, in particular xanthan gum, guar guar, agar agar, alginates and tyloses, carboxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose, and also relatively high molecular weight polyethylene glycol mono- and diesters of fatty acids, polyacrylates (e.g. Carbopols® and Pemulen grades from Goodrich; Synthalens® from Sigma; Keltrol grades from Kelco; Sepigel grades from Seppic; Salcare grades from Allied Colloids), polyacrylamides, polymers, polyvinyl alcohol and polyvinylpyrrolidone. Bentonites, such as, for example, Bentone® Gel VS 5PC (Rheox), which is a mixture of cyclopentasiloxane, disteardimonium hectorite and propylene carbonate, have also proven to be particularly effective. Also suitable are surfactants, such as, for example, ethoxylated fatty acid glycerides, esters of fatty acids with polyols such as, for example, pentaerythritol or trimethylolpropane, fatty alcohol ethoxylates having a narrowed homologue distribution or alkyl oligoglucosides, and electrolytes such as sodium chloride and ammonium chloride.

Superfatting Agents

Superfatting agents which can be used are substances such as, for example, lanolin and lecithin, and polyethoxylated or acylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides and fatty acid alkanolamides, the latter also serving as foam stabilizers.

Stabilizers

Stabilizers which can be used are metal salts of fatty acids, such as, for example, magnesium, aluminium and/or zinc stearate or ricinoleate.

Polymers

Suitable cationic polymers are, for example, cationic cellulose derivatives, such as, for example, a quaternized hydroxyethylcellulose obtainable under the name Polymer JR 400® from Amerchol, cationic starch, copolymers of diallylammonium salts and acrylamides, quaternized vinylpyrrolidone-vinylimidazole polymers, such as, for example, Luviquat® (BASF), condensation products of polyglycols and amines, quaternized collagen polypeptides, such as, for example, lauryldimonium hydroxypropyl hydrolyzed collagen (Lamequat@UGrunau), quaternized wheat polypeptides, polyethyleneimine, cationic silicone polymers, such as, for example, amodimethicones, copolymers of adipic acid and dimethylaminohydroxypropyldiethylenetriamine (Cartaretins@/Sandoz), copolymers of acrylic acid with dimethyldiallylammonium chloride (Merquat® 550/Chemviron), polyaminopolyamides, as described, for example, in FR 2252840 A, and crosslinked water-soluble polymers thereof, cationic chitin derivatives, such as, for example, quaternized chitosan, optionally in microcrystalline dispersion, condensation products from dihaloalkyls, such as, for example, dibromobutane with bisdialkylamines, such as, for example, bis-dimethylamino-1,3-propane, cationic guar gum, such as, for example, Jaguar® CBS, Jaguar® C-17, Jaguar® C-16 from Celanese, quaternized ammonium salt polymers, such as, for example, Mirapol® A-15, Mirapol® AD-1, Mirapol® AZ-1 from Miranol.

Suitable anionic, zwitterionic, amphoteric and nonionic polymers are, for example, vinyl acetate-crotonic acid copolymers, vinylpyrrolidone-vinyl acrylate copolymers, vinyl acetate-butyl. maleate-isobornyl acrylate copolymers, methyl vinyl ether-maleic anhydride copolymers and esters thereof, uncrosslinked polyacrylic acids and polyacrylic acids crosslinked with polyols, acrylamidopropyltrimethylammonium chloride-acrylate copolymers, octylacrylamide-methyl methacrylate-tert-butylaminoethyl methacrylate-2-hydroxypropyl methacrylate copolymers, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, vinylpyrrolidone-dimethylaminoethyl methacrylate-vinylcaprolactam terpolymers, and optionally derivatized cellulose ethers and silicones.

Silicone Compounds

Suitable silicone compounds are, for example, dimethylpolysiloxanes, methylphenylpolysiloxanes, cyclic silicones, and amino-, fatty acid-, alcohol-, polyether-, epoxy-, fluorine-, glycoside- and/or alkyl-modified silicone compounds, which can either be liquid or in resin form at room temperature. Also suitable are simethicones, which are mixtures of dimethicones having an average chain length of from 200 to 300 dimethylsiloxane units and hydrogenated silicates.

UV Photoprotective Filters

UV photoprotective factors are, for example, to be understood as meaning organic substances (photoprotective filters) which are liquid or crystalline at room temperature and which are able to absorb ultraviolet rays and give off the absorbed energy again in the form of longer-wavelength radiation, e.g. heat. UVB filters can be oil-soluble or water-soluble. Examples of oil-soluble substances are:

-   -   3-benzylidenecamphor or 3-benzylidenenorcamphor and derivatives         thereof, e.g. 3-(4-methylbenzylidene)camphor;     -   4-aminobenzoic acid derivatives, preferably 2-ethylhexyl         4(dimethylamino)benzoate, 2-octyl 4-(dimethylamino)benzoate and         amyl 4(dimethylamino)benzoate;     -   esters of cinnamic acid, preferably 2-ethylhexyl         4-methoxycinnamate, propyl 4-methoxycinnamate, isoamyl         4-methoxycinnamate, 2-ethylhexyl 2-cyano-3,3-phenylcinnamate         (octocrylene);     -   esters of salicylic acid, preferably 2-ethylhexyl salicylate,         4-isopropylbenzyl salicylate, homomethyl salicylate;     -   derivatives of benzophenone, preferably         2-hydroxy-4-methoxybenzophenone,         2hydroxy-4-methoxy-4′-methylbenzophenone,         2,2′-dihydroxy-4-methoxybenzophenone;     -   esters of benzalmalonic acid, preferably di-2-ethylhexyl         4-methoxybenzalmalonate;     -   triazine derivatives, such as, for example,         2,4,6-trianilino(p-carbo-2¹-ethyl-1′ hexyloxy)-1,3,5-triazine         and octyltriazone or dioctylbutamidotriazone (Uvasorb® HEB);     -   propane-1,3-diones, such as, for example,         1-(4-tert-butylphenyl)-3-(4′methoxyphenyl) propane-1,3-dione;     -   ketotricyclo(5.2.1.0)decane derivatives.     -   Suitable water-soluble substances are:     -   2-phenylbenzimidazole-5-sulphonic acid and the alkali metal,         alkaline earth metal, ammonium, alkylammonium, alkanolammonium         and glucammonium salts thereof;     -   sulphonic acid derivatives of benzophenones, preferably         2-hydroxy-4-methoxybenzophenone-5-sulphonic acid and its salts;     -   sulphonic acid derivatives of 3-benzylidenecamphor, such as, for         example, 4-(2oxo-3-bornylidenemethyl)benzenesulphonic acid and         2-methyl-5-(2-oxo-3-bornylidene) sulphonic acid and salts         thereof.

Suitable typical UV-A filters are, in particular, derivatives of benzoylmethane, such as, for example, 1-(4′-tert-butylphenyl)-3-(4′-methoxyphenyl)propane-1,3-dione, 4tert-butyl-4′-methoxydibenzoylmethane (Parsol® 1789), 1-phenyl-3-(4′ isopropylphenyl) propane-1,3-dione, and enamine compounds. The UV-A and UV-B filters can of course also be used in mixtures. Particularly favourable combinations consist of the derivatives of benzoylmethane, e.g. 4-tert-butyl-4′-methoxydibenzoylmethane (Parsol® 1789) and 2-ethylhexyl 2-cyano-3,3-cinnamate (octocrylene) in combination with esters of cinnamic acid, preferably 2-ethylhexyl 4-methoxycinnamate and/or propyl 4-methoxycinnamate and/or isoamyl 4-methoxycinnamate. Advantageously, such combinations are combined with watersoluble filters such as, for example, 2-phenylbenzimidazole-5-sulphonic acid and their alkali metal, alkaline earth metal, ammonium, alkylammonium, alkanolammonium and glucammonium salts.

As well as said soluble substances, insoluble light protection pigments, namely finely dispersed metal oxides or salts, are also suitable for this purpose. Examples of suitable metal oxides are, in particular, zinc oxide and titanium dioxide and also oxides of iron, zirconium, silicon, manganese, aluminium and cerium, and mixtures thereof. Salts which may be used are silicates (talc), barium sulphate or zinc stearate. The oxides and salts are used in the form of the pigments for skincare and skin-protective emulsions and decorative cosmetics. The particles here should have an average diameter of less than 100 nm, preferably between 5 and 50 nm and in particular between 15 and 30 nm. They can have a spherical shape, but it is also possible to use particles which have an ellipsoidal shape or a shape deviating in some other way from the spherical form. The pigments can also be surface-treated, i.e. hydrophilicized or hydrophobicized. Typical examples are coated titanium dioxides, such as, for example, titanium dioxide T 805 (Degussa) or Eusolex® T2000 (Merck). Suitable hydrophobic coating agents are here primarily silicones and, specifically in this case, trialkoxyoctylsilanes or simethicones. In sunscreens, preference is given to using so-called micro- or nanopigments. Preference is given to using micronized zinc oxide.

Biogenic Active Ingredients and Antioxidants

Biogenic active ingredients are understood as meaning, for example, tocopherol, tocopherol acetate, tocopherol palmitate, ascorbic acid, (deoxy)ribonucleic acid and fragmentation products thereof, f3-glucans, retinol, bisabolol, allantoin, phytantriol, panthenol, AHA acids, amino acids, ceramides, pseudoceramides, essential oils, plant extracts, such as, for example, prunus extract, bambara nut extract and vitamin complexes.

Antioxidants interrupt the photochemical reaction chain which is triggered when UV radiation penetrates the skin. Typical examples thereof are amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g. urocanic acid) and derivatives thereof, peptides, such as D,L-carnosine, D-carnosine, Lcarnosine and derivatives thereof (e.g. anserine), carotenoids, carotenes (e.g. acarotene, I3-carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof (e.g. dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (e.g. thioredoxin, glutathione, cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, γ-linoleyl, cholesteryl and glyceryl esters thereof) and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts), and sulphoximine compounds (e.g. buthionine sulphoximines, homocysteine sulphoximine, buthionine suiphones, penta-, hexa-, heptathionine sulphoximine) in very low tolerated doses (e.g. pmol to).Imol/kg), and also (metal) chelating agents (e.g. a-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), a-hydroxy acids (e.g. citric acid, lactic acid, malic acid), humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g. y-linolenic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives (e.g. ascorbyl palmitate, Mg ascorbyl phosphate, ascorbyl acetate), tocopherols and derivatives (e.g. vitamin E acetate), vitamin A and derivatives (vitamin A palmitate), and coniferyl benzoate of gum benzoin, rutic acid and derivatives thereof, a-glycosylrutin, ferulic acid, furfurylideneglucitol, carnosine, butylhydroxytoluene, butylhydroxyanisole, nordihydroguaiacic acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, superoxide dismutase, zinc and derivatives thereof (e.g. ZnO, ZnS04) selenium and derivatives thereof (e.g. selenomethionine), stilbenes and derivatives thereof (e.g. stilbene oxide, trans-stilbene oxide) and the derivatives (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids) of said active ingredients which are suitable according to the invention.

Deodorants and Antimicrobial Agents

Cosmetic deodorants counteract, mask or remove body odours. Body odours arise as a result of the effect of skin bacteria on apocrine perspiration, with the formation of degradation products which have an unpleasant odour. Accordingly, deodorants comprise active ingredients which act as antimicrobial agents, enzyme inhibitors, odour absorbers or odour masking agents.

Antimicrobial Agents

Suitable antimicrobial agents are, in principle, all substances effective against gram-positive bacteria, such as, for example, 4-hydroxybenzoic acid and its salts and esters, N-(4-chlorophenyl)-N′-(3,4-dichlorophenyl)urea, 2,4,4′-trichloro-2′ hydroxydiphenyl ether (triclosan), 4-chloro-3,5-dimethylphenol, 2,2′-methylenebis(6-bromo-4-chlorophenol), 3-methyl-4-(1-methylethyl)phenol, 2-benzyl-4-chlorophenol, 3-(4-chlorophenoxy)-1,2-propanediol, 3-iodo-2-propynyl butylcarbamate, chlorhexidine, 3,4,4′-trichlorocarbanilide (TTC), antibacterial fragrances, thymol, thyme oil, eugenol, oil of cloves, menthol, mint oil, famesol, phenoxyethanol, glycerol monocaprate, glycerol monocaprylate, glycerol monolaurate (GML), diglycerol monocaprate (DMC), salicylic acid N-alkylamides, such as, for example, N-octylsalicylamide or N-decylsalicylamide.

Enzyme Inhibitors

Suitable enzyme inhibitors are, for example, esterase inhibitors. These are preferably trialkyl citrates, such as trimethyl citrate, tripropyl citrate, triisopropyl citrate, tributyl citrate and, in particular, triethyl citrate (Hydagen@ CAT). The substances inhibit enzyme activity, thereby reducing the formation of odour. Other substances which are suitable esterase inhibitors are sterol sulphates or phosphates, such as, for example, lanosterol, cholesterol, campesterol, stigmasterol and sitosterol sulphate or phosphate, dicarboxylic acids and esters thereof, such as, for example, glutaric acid, monoethyl glutarate, diethyl glutarate, adipic acid, monoethyl adipate, diethyl adipate, malonic acid and diethyl malonate, hydroxycarboxylic acids and esters thereof, such as, for example, citric acid, malic acid, tartaric acid or diethyl tartrate, and zinc glycinate.

Odour Absorbers

Suitable odour absorbers are substances which are able to absorb and largely retain odour-forming compounds. They lower the partial pressure of the individual components, thus also reducing their rate of diffusion. It is important that in this process perfumes must remain unimpaired. Odour absorbers are not effective against bacteria. They comprise, for example, as main constituent, a complex zinc salt of ricinoleic acid or specific, largely odour-neutral fragrances which are known to the person skilled in the art as “fixatives”, such as, for example, extracts of labdanum or styrax or certain abietic acid derivatives. The odour masking agents are fragrances or perfume oils, which, in addition to their function as odour masking agents, give the deodorants their respective fragrance note. Perfume oils which may be mentioned are, for example, mixtures of natural and synthetic fragrances. Natural fragrances are extracts from flowers, stems and leaves, fruits, fruit peels, roots, woods, herbs and grasses, needles and branches, and resins and balsams. Also suitable are animal raw materials, such as, for example, civet and castoreum. Typical synthetic fragrance compounds are products of the ester, ether, aldehyde, ketone, alcohol and hydrocarbon type. Fragrance compounds of the ester type are, for example, benzyl acetate, p-tert-butylcyclohexyl acetate, linalyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, allyl cyclohexylpropionate, styrallyl propionate and benzyl salicylate. The ethers include, for example, benzyl ethyl ether, and the aldehydes include, for example, the linear alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial and bourgeonal, the ketones include, for example, the ionones and methyl cedryl ketone, the alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol and terpineol, and the hydrocarbons include mainly the terpenes and balsams. Preference is, however, given to using mixtures of different fragrances which together produce a pleasing fragrance note. Essential oils of relatively low volatility, which are mostly used as aroma components, are also suitable as perfume oils, e.g. sage oil, camomile oil, oil of cloves, melissa oil, mint oil, cinnamon leaf oil, linden blossom oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, labdanum oil and lavandin oil. Preference is given to using bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, 0.hexylcinnamaldehyde, geraniol, benzylacetone, cyclamen aldehyde, linalool, boisambrene forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclovertal, lavandin oil, clary sage oil, f3damascone, geranium oil bourbon, cyclohexyl salicylate, Vertofix coeur, iso-Esuper, Fixolide NP, evernyl, iraldein gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romilat, irotyl and floramat alone or in mixtures.

Antiperspirants

Antiperspirants reduce the formation of perspiration by influencing the activity of the eccrine sweat glands, thus counteracting underarm wetness and body odor. Aqueous or anhydrous formulations of antiperspirants typically comprise the following ingredients:

-   -   astringent active ingredients,     -   oil components,     -   nonionic emulsifiers,     -   coemulsifiers,     -   consistency regulators,     -   auxiliaries, such as, for example, thickeners or complexing         agents and/or     -   nonaqueous solvents, such as, for example, ethanol, propylene         glycol and/or glycerol.

Suitable astringent antiperspirant active ingredients are primarily salts of aluminium, zirconium or of zinc. Such suitable antihydrotic active ingredients are, for example, aluminium chloride, aluminium chlorohydrate, aluminium dichlorohydrate, aluminium sesquichlorohydrate and complex compounds thereof, e.g. with 1,2-propylene glycol, aluminium hydroxyallantoinate, aluminium chloride tartrate, aluminium zirconium trichlorohydrate, aluminium zirconium tetrachlorohydrate. aluminium zirconium pentachlorohydrate and complex compounds thereof, e.g. with amino acids, such as glycine. In addition, customary oil-soluble and water-soluble auxiliaries may be present in antiperspirants in relatively small amounts. Such oil-soluble auxiliaries may, for example, be:

-   -   anti-inflammatory, skin-protective or perfumed essential oils,     -   synthetic skin-protective active ingredients and/or     -   oil-soluble perfume oils.

Customary water-soluble additives are, for example, preservatives, water-soluble fragrances, pH regulators, e.g. buffer mixtures, water-soluble thickeners. e.g. water-soluble natural or synthetic polymers, such as, for example, xanthan gum, hydroxyethylcellulose, polyvinylpyrrolidone or high molecular weight polyethylene oxides.

Film Formers

Customary film formers are, for example, chitosan, microcrystalline chitosan, quaternized chitosan, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, polymers of the acrylic acid series, quaternary cellulose derivatives, collagen, hyaluronic acid and salts thereof, and similar compounds.

Antidandruff Active Ingredients

Suitable antidandruff active ingredients are piroctone olamine (1-hydroxy-4-methyl6-(2,4,4-trimythylpentyl)-2-(1H)-pyridinone monoethanolamine salt), Baypival® (c1 imbazole), Ketoconazole®, (4-acetyl-1-{-4-[2-(2,4-dichlorophenyl) r-2-(1H-imidazo1′-ylmethyl)-1,3-dioxylan-c-4-ylmethoxyphenyl}piperazine, ketoconazole, elubiol, selenium disulphide, sulphur colloidal, sulphur polyethylene glycol sorbitan monooleate, sulphur ricinole polyethoxylate, sulphur tar distillates, salicylic acid (or in combination with hexachlorophene), undecylenic acid monoethanolamide sulphosuccinate Na salt, Lamepon® UD (protein undecylenic acid condensate), zinc pyrithione, aluminium pyrithione and magnesium pyrithione/dipyrithione magnesium sulphate.

Swelling Agents

The swelling agents for aqueous phases may be montmorillonites, clay mineral substances, Pemulen, and alkyl-modified Carbopol grades (Goodrich). Other suitable polymers and swelling agents are given in the review by R. Lochhead in Cosm. Toil. 108, 95 (1993).

Insect Repellents

Suitable insect repellents are N,N-diethyl-m-toluamide, 1,2-pentanediol or ethyl butylacetylaminopropionate.

Self-Tanning Agents and Depigmentation Agents

A suitable self-tanning agent is dihydroxyacetone. Suitable tyrosine inhibitors, which prevent the formation of melanin and are used in depigmentation agents, are, for example, arbutin, ferulic acid, kojic acid, coumaric acid and ascorbic acid (vitamin C).

Hydrotropic Agents

To improve the flow behaviour, it is also possible to use hydrotropic agents, such as, for example, ethanol, isopropyl alcohol, or polyols. Polyols which are suitable here preferably have 2 to 15 carbon atoms and at least two hydroxyl groups. The polyols can also contain further functional groups, in particular amino groups, or be modified with nitrogen. Typical examples are

-   -   glycerol;     -   alkylene glycols, such as, for example, ethylene glycol,         diethylene glycol, propylene glycol, butylene glycol, hexylene         glycol, and polyethylene glycols with an average molecular         weight of from 100 to 1 000 daltons;     -   technical-grade oligoglycerol mixtures with a degree of         self-condensation of from 1.5 to 10, such as, for example,         technical-grade diglycerol mixtures with a diglycerol content of         from 40 to 50% by weight;     -   methylol compounds, such as, in particular, trimethylolethane,         trimethylolpropane, trimethylolbutane, pentaerythritol and         dipentaerythritol;     -   lower alkyl glucosides, in particular those having 1 to 8 carbon         atoms in the alkyl radical, such as, for example, methyl and         butyl glucoside;     -   sugar alcohols having 5 to 12 carbon atoms, such as, for         example, sorbitol or mannitol,     -   sugars having 5 to 12 carbon atoms, such as, for example,         glucose or sucrose;     -   amino sugars, such as, for example, glucamine;     -   dialcohol amines, such as diethanolamine or         2-amino-1,3-propanediol.

Preservatives

Suitable preservatives are, for example, phenoxy ethanol, formaldehyde solution, parabens, pentanediol or sorbic acid, and the silver complexes known under the name Surfacins®, and also the other classes of substance listed in Annex 6, Part A and B of the Cosmetics Directive.

Perfume Oils and Aromas

Perfume oils which may be mentioned are mixtures of natural and synthetic fragrances. Natural fragrances are extracts from flowers (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (aniseed, coriander, cumin, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamon, costus, iris, calmus), woods (pinewood, sandalwood, guaiac wood, cedarwood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf-pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Also suitable are animal raw materials, such as, for example, civet and castoreum. Typical synthetic fragrance compounds are products of the ester, ether, aldehyde, ketone, alcohol and hydrocarbon type. Fragrance compounds of the ester type are, for example, benzyl acetate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, ethylmethylphenyl glycinate, allyl cyclohexylpropionate, styrallyl propionate and benzyl salicylate. The ethers include, for example, benzyl ethyl ether, the aldehydes include, for example, the linear alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial and bourgeonal, and the ketones include, for example, the ionones, aisomethylionone and methyl cedryl ketone, the alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol and terpineol, and the hydrocarbons include mainly the terpenes and balsams. Preference is, however, given to using mixtures of different fragrances which together produce a pleasing fragrance note. Essential oils of relatively low volatility, which are mostly used as aroma components, are also suitable as perfume oils, e.g. sage oil, camomile oil, oil of cloves, melissa oil, mint oil, cinnamon leaf oil, linden blossom oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, labolanum oil and lavandin oil. Preference is given to using bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, a-hexylcinnamaldehyde, geraniol, benzylacetone, cyclamen aldehyde, linalool, boisambrene forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclovertal, lavandin oil, clary sage oil, 13-damascone, geranium oil bourbon, cyclohexyl salicylate, Vertofix coeur, iso-Esuper, Fixolide NP, evernyl, iraldein gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romilat, irotyl and floramat alone or in mixtures.

Suitable aromas are, for example, peppermint oil, spearmint oil, anise oil, star anise oil, caraway oil, eucalyptus oil, fennel oil, lemon oil, wintergreen oil, oil of cloves, menthol and the like.

Dyes

Dyes which can be used are the substances which are approved and suitable for cosmetic purposes, as are summarized, for example, in the publication “Kosmetische Farbemittel” [Cosmetic Colorants] from the Farbstoffkommission der Deutschen Forschungsgemeinschaft [Dyes Commission of the German Research Council], Verlag Chemie, Weinheim, 1984, pp. 81-106. Examples are cochineal red A (C.1.16255), patent blue V (C.1.42051), indigotin (C.1.73015), chlorophyllin (C.1.75810), quinoline yellow (C.1.47005), titanium dioxide (C.1.77891), indanthrene blue RS (C.1.69800) and madder lake (C.1.58000). As a luminescent dye, it is also possible for luminol to be present. These dyes are customarily used in concentrations of from 0.001 to 0.1% by weight, based on the total mixture.

The total amount of auxiliaries and additives can be 1 to 50% by weight, preferably 5 to 40% by weight, based on the compositions. The compositions can be prepared by customary cold or hot processes; preference is given to using the phase-inversion temperature method.

EXAMPLES Effects on the Growth of Human Primary Keratinocytes

The aim of this test was to analyse the revitalizing and regenerating activities of oligpopeptides according to the invention on human keratinocyte cultures in vitro.

Human keratinocytes were obtained by trypsinization of skin biopsies. They were incubated in standard medium for cell cultures with foetal calf serum (FCS) and growth factors (EGF 10 ng/ml). After cultivation for 2 days at 37° C. and a CO₂ content of 5%, the medium was replaced by standard medium with varying concentrations of peptides. After a further incubation of 4 or 5 days at 37° C. and a CO₂ content of 5%, the number of living cells was determined by determining the cellular DNA content using an ethidium bromide fluorescent sample. The fluorescence was determined using a fluorimeter (excitation at 538 nm and emission at 590 nm). The foetal calf serum forms a positive control because it comprises many growth factors, such as, for example, IGF (insulin-like growth factor) and PDGF (platelet derived growth factor).

The results are shown in Table 1 and 2 as the average value from 3 assays in triplicate in % based on a control in which the standard medium comprised no additives.

TABLE 1 DNA after Concentration culture Oligopeptide % (w/v) for 4-5 days Control — 100 Foetal calf serum 1    117 +/− 13 Example 1 Arg-Arg-Arg-Pro-Arg-Pro-Pro- 0.001 124 +/− 15 Tyr-Leu-Pro-Arg-Pro-Arg-Pro- 0.003 131 +/− 11 Pro (SEQ ID NO. 341) Example 2 0.001 119 +/− 6  Arg-Arg-Arg-Pro-Arg (SEQ ID NO. 38) 0.003 126 +/− 8  Example 3 0.001 97 +/− 1 Arg-Pro-Pro-Tyr-Leu (SEQ ID NO. 42) 0.003 118 +/− 10 Example 4 0.001 150 +/− 26 Pro-Pro-Tyr-Leu (SEQ ID NO. 7) 0.003 166 +/− 7  Example 5 0.001 118 +/− 3  Pro-Tyr-Leu-Pro-Arg (SEQ ID NO. 44) 0.003 112 +/− 5  Example 6 0.001 110 +/− 6  Tyr-Leu-Pro-Arg-Pro (SEQ ID NO. 45) 0.003 146 +/− 24

TABLE 2 Concentration DNA after culture Peptide % (w/v) for 3 days Control — 100 Foetal calf serum 1     126 +/− 17 Example 7 0.00005 136 +/− 13 N-Palmitoyl-Pro-Pro-Tyr-Leu 0.00015 135 +/− 8  (SEQ ID NO. 374)

The oligopeptide consisting of 15 consecutive amino acids of SEQ ID NO.1 (Example 1, R1=H, R2=OH) as well as the oligopeptides consisting of 5 consecutive amino acids, which are identical to 5 consecutive amino acids of SEQ ID NO.1 (examples 2, 3, 5 and 6, R1=H, R2=OH) as well as the oligopeptides consisting of 4 consecutive amino acids, which are identical to 4 consecutive amino acids of SEQ ID NO.1 (example 4, R1=H, R2=OH) stimulate the growth of human keratinocytes cultivated from biopsies of adult subjects. The activity can still be detected after 5 days even without changing the cell culture medium.

The same is true for an oligopeptide according to formula (I), wherein [AA] is Pro-Pro-Tyr-Leu (SEQ ID NO.7); , R1 is Palmitoyl and R2 is OH (=example 7).

Stimulation of the Synthesis of Syndecan-1 on Human Keratinocytes

Monoclonal antibody anti-syndecan-1 and secondary antibody FITC conjugated were obtained from TEBU, Le Perray en Yvelines and BIO-RAD, Marnes-1a-Coquette; KGF (Keratinocyte Growth Factor) (positive control) was obtained from SIGMA, L′Isle d'Abeau Chesnes.

Human keratinocytes were seeded in DMEM standard medium for 2 days at 37° C., CO₂=5%. Then, N-Acetyl-Pro-Pro-Tyr-Leu (SEQ ID NO. 375) or positive control KGF are introduced and after 5 days of incubation at 37° C., CO₂=5%, the synthesis of syndecan-1 was evaluated on glass slides by immunocytochemistry. Quantification of the staining was carried out by image analysis.

The results are shown in table 3 as the mean of the sum ±SEM of the product of number of pixels by green detected values (arbitrary unit).

TABLE 3 Control Treated with without KGF at 10 Treated with N-Acetyl- treatment ng/ml (positive Pro-Pro-Tyr-Leu (DMEM) control) 1 μg/ml 3 μg/ml Sum of product of 1 545 10³ ± 2408 10³ ± 2791 10³ ± 3344 10³ ± number of pixel by 374 10³ 549 10³ 573 10³ 359 10³ (*) green detected values for syndecan-1 (arbitrary unit) Statistics: Test PLSD of Fisher (*)/control, p < 0.01

Without treatment, human keratinocytes in culture expressed a small amount of syndecan-1. The treatment with the positive control KGF has induced an increase of syndecan-1 expression in the keratinocytes culture.

The oligopeptide according formula (I) wherein [AA] is Pro-Pro-Tyr-Leu (SEQ ID NO. 7); R1 is Acetyl and R2 is OH stimulates the synthesis of syndecan-1 in human keratinocytes cultivated from biopsies of adult subjects.

% by weight Cosmetic emulsion: Trade Name [INCI] Emulgade SE-PF (2) 6.00 [Glyceryl Stearate (and) Ceteareth-20 (and) Ceteareth-12 (and) Cethaeryl Alcohol (and) Cetyl palmitate] Lanette 0⁽²⁾ 2.50 [Cetearyl Alcohol] Cegesoft C24⁽²⁾ 6.00 [Ethyl hexyl palmitate] Cetiol PGL⁽²⁾ 5.00 [Hexyldecanol (and) Hexyldecyl laurate] Myritol 312⁽²⁾ 3.00 [Caprylic/Capric Triglyceride] DC 200-50cts⁽³⁾ 1.00 [Dimethicone] Deioinzed water add 100 Keltrol T⁽⁴⁾ 0.20 [Xantham Gum] Elestab 50J⁽¹⁾ 0.40 [Chlorphensin (and) Methylparaben] Glycerine 4.00 Carbopol 980⁽⁵⁾ 2% 15.00 [Carbomer] NaOH 10% 0.60 Perfume Champaline G10415611⁽⁶⁾ 0.10 N-Acetyl-Pro-Pro-Tyr-Leu-OH 0.0003 Cosmetic fluid serum Trade Name Deionized water add 100 Elestab 50J⁽¹⁾ 0.35 [Chlorphenesin (and) Methylparaben] H-Tyr-Leu-Pro-Arg-Pro-OH 0.001 Keltrol CGT⁽⁴⁾ 0.10 [Xantham gum] Cosmedia SP⁽²⁾ 0.25 [Sodium Polyacrylate] Suppliers ⁽¹⁾Laboratoires Serobiologiques ⁽²⁾Cognis ⁽³⁾Dow Corning ⁽⁴⁾Kelco ⁽⁵⁾Noveon ⁽⁶⁾Robertet

SEQ 10 No.1 consisting of 39 amino acids:

(=1)Arg Arg Arg Pro Arg Pro Pro Tyr Leu Pro Arg Pro Arg Pro Pro Pro Phe Phe Pro Pro Arg Leu Pro Pro Arg He Pro Pro Glu Phe Pro Pro Arg Phe Pro Pro Arg Phe Pro (=39) 

1. A cosmetic composition comprising oligopeptides with the structure of formula (I) R1-[AA]_(n)-R2  (I) wherein [AA] comprises at least 5 consecutive amino acids, which are identical compared to 5 consecutive amino acids of SEQ 10 NO. 1, wherein n is the total number of amino acids in the oligopeptide, wherein n=5; wherein R1 is linked to the amino-terminal part of [AA] and is selected from the group consisting of a) —H, b) a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24 carbon atoms, wherein said acyl group is optionally functionalised by a —OH, —SH, —COOH or —CONH₂ group, and c) a sterol or a sphingolipid group which is joined to the amino terminal part of [AA] via a bifunctional linker, and wherein R2 is linked to the C═O group of the carboxy terminal part of [AA] and is selected from the group consisting of d) —OH, e) —NH₂, f) a linear saturated or unsaturated or branched saturated or unsaturated alkoxy group having 1 to 24 carbon atoms, wherein said acyl group is optionally functionalised by a —OH, —SH, —COOH or CONH₂ group, and g) a sterol or a sphingolipid group.
 2. The composition of claim 1, wherein [AA] comprises at least 5 consecutive amino acids identical to amino acids no. 1 to 15 of SEQ ID0 NO.1.
 3. The composition of claim 1, wherein R1=H or a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 12 carbon atoms.
 4. The composition of claim 3, wherein R1=H and R2=OH.
 5. The composition of claim 1, wherein the oligopeptides are present in a concentration of from 0.05 to 500 ppm.
 6. The composition of claim 5, wherein the oligopeptides are present in a concentration of from 0.5 to 100 ppm.
 7. The composition of claim 1 which is selected from the group consisting of shampoos, hair lotions, foam baths, shower baths, creams, gels, lotions, alcoholic and aqueous/alcoholic solutions, emulsions, wax/fat masses, stick preparations, powders and ointments.
 8. The composition of claim 1, wherein said oligopeptides are present in an amount effective to stimulate the growth of human keratinocytes in-vitro.
 9. The composition of claim 1, wherein said at least 5 consecutive amino acids is selected from the group consisting of Arg-Arg-Arg-Pro-Arg (SEQ ID NO. 38), Arg-Pro-Pro-Tyr-Leu (SEQ ID NO. 42), Pro-Tyr-Leu-Pro-Arg (SEQ ID NO. 44), and Tyr-Leu-Pro-Arg-Pro (SEQ ID NO. 45).
 10. A cosmetic composition comprising oligopeptides with the structure of formula (I) R1-[AA]_(n)-R2  (I) wherein [AA] comprises at least 5 consecutive amino acids, which are identical compared to 5 consecutive amino acids of SEQ ID NO. 1, wherein n is the total number of amino acids in the oligopeptide, wherein n=5, wherein R1 is linked to the amino-terminal part of [AA] and is selected from the group consisting of a. —H, b. a linear saturated or unsaturated or branched saturated or unsaturated acyl group having 1 to 24 carbon atoms, which may be functionalised by a —OH, —SH, —COOH or —CONH₂ group, or c. a sterol or a sphingolipid group which is joined to the amino terminal part of [AA] via a bifunctional linker, wherein R2 is linked to the C═O group of the carboxy terminal part of [AA] and is selected from the group consisting of d) —OH, e) —NH₂, f) a linear saturated or unsaturated or branched saturated or unsaturated alkoxy group having 1 to 24 carbon atoms, which may be functionalised by a —OH, SH, —COOH or —CONH₂ group, and g) a sterol or a sphingolipid group, with the proviso that if R1 is —H, R2 is not —OH; or that if R2 is —OH, R1 is not —H; and with the further proviso that if R1 is —H, R2 is selected from the group consisting of h) —NH₂, i) a linear saturated or unsaturated or branched saturated or unsaturated alkoxy group having 2 to 24 carbon atoms, and j) a sterol or a sphingolipid group.
 11. The composition of claim 10, wherein the oligopeptides are present in a concentration of from 0.05 to 500 ppm.
 12. The composition of claim 11, wherein the oligopeptides are present in a concentration of from 0.5 to 100 ppm.
 13. A method for strengthening the cutaneous barrier of human skin comprising contacting the skin with the cosmetic composition of claim 1 in an amount effective to stimulate the growth and differentiation of human keratinocytes.
 14. A method for strengthening the cutaneous barrier of human skin comprising contacting the skin with the cosmetic composition of claim 1 in an amount effective to stimulate syndecan-1 synthesis.
 15. A method for delaying and preventing skin aging and strengthening firmness, epidermal cohesion, and dermo-epidermal junction of human skin comprising contacting the skin with the cosmetic composition of claim 1 in an amount effective to stimulate the growth and differentiation of human keratinoctyes.
 16. A method for delaying and preventing skin aging and strengthening firmness, epidermal cohesion, and dermo-epidermal junction of human skin comprising contacting the skin with the cosmetic composition of claim 1 in an amount effective to stimulate syndecan-1 synthesis.
 17. An oligopeptide selected from the group consisting of Arg-Arg-Arg-Pro-Arg (SEQ ID NO. 38), Arg-Pro-Pro-Tyr-Leu (SEQ ID NO. 42), Pro-Tyr-Leu-Pro-Arg (SEQ ID NO. 44), and Tyr-Leu-Pro-Arg-Pro (SEQ ID NO. 45). 